Abstract
Background:
Extensive ablation in addition to pulmonary vein isolation (PVI) would be effective for modification of non-pulmonary vein (non-PV) substrates, whereas PVI might be sufficient for elimination of PV triggers. This study aimed to test the hypothesis that in patients with reproducible atrial fibrillation (AF) triggered by premature atrial contractions originating only from PVs, PVI alone can be sufficient to maintain sinus rhythm.
Methods and Results:
This study is a prespecified subanalysis of the EARNEST-PVI randomized controlled trial. This study investigated the efficacy of the PVI-alone strategy (PVI-alone) in comparison with the extensive strategy (PVI-plus) for persistent AF with a trigger-based mechanism vs. a substrate-based mechanism. Patients were stratified into 3 groups based on AF mechanisms: (1) Substrate group (N=236); (2) PV trigger group (N=236); and (3) non-PV trigger group (N=24). The hazard ratios for AF recurrence of the PVI-alone strategy with reference to the PVI-plus strategy were 1.456 (95% confidence interval [CI] [0.864–2.452]) in the substrate group, 1.648 (95% CI 0.969–2.801) in the PV trigger group, and 0.937 (95% CI 0.252–3.488) in the non-PV trigger group. No significant interaction between ablation strategy and AF mechanism was observed (P for interaction=0.748).
Conclusions:
This study indicated that the efficacies of the PVI-alone strategy compared with the PVI-plus strategy were consistent across persistent AF with trigger-based and substrate-based mechanisms.
The efficacy of extensive ablation in addition to pulmonary vein isolation (PVI) for maintenance of sinus rhythm in catheter ablation (CA) for persistent atrial fibrillation (AF) has not been established.1–3
The most recent clinical guidelines and expert consensus do not recommend routine ablation of linear lesions, complex fractionated atrial electrograms (CFAE), rotational activity, or autonomic ganglia.4
The EARNEST-PVI (Effect of Extensive Ablation on Recurrence in Patients with Persistent AF Treated with Pulmonary Vein Isolation) randomized controlled trial investigated whether PVI alone was non-inferior to more extensive ablation with respect to the maintenance of sinus rhythm in patients with persistent AF. However, the trial failed to establish the non-inferiority of the PVI-alone strategy compared to the extensive ablation strategy, but rather showed possible superiority of the extensive ablation strategy, albeit its non-inferiority study design.5
Although the main analysis of the EARNEST-PVI trial did not reach the primary endpoint, the efficacy of empiric ablation of linear lesions and CFAE, in addition to PVI, was implied to be inconsistent with the previous studies.1–3
This inconsistency could be due to some heterogeneity in the efficacy of the ablation strategy in patients with different characteristics and mechanisms of persistent AF. We hypothesized that although extensive ablation, in addition to PVI, would be effective for modification of non-pulmonary vein (non-PV) substrates, PVI might be sufficient for elimination of PV triggers in patients with reproducible AF triggered by premature atrial contractions (PACs) originating from the PVs only. This study is a prespecified subanalysis of the EARNET-PVI trial to test the hypothesis.
Methods
Study Design
The EARNEST-PVI trial was a prospective, multicenter, randomized, open-label non-inferiority trial of patients with persistent AF undergoing an initial CA procedure. The study design has been published previously.5,6
The study was conducted by the Osaka Cardiovascular Conference Arrhythmia Investigators. Informed consent was obtained from each patient prior to any trial-related procedure. After providing informed consent at each hospital, patients who were eligible for the trial were randomized to either a PVI alone (PVI-alone strategy) arm or a PVI plus additional ablation arm (PVI-plus strategy) in a 1 : 1 fashion. The study was registered at ClinicalTrials.gov (NCT03514693), approved by the institutional review board of each participating hospital, and performed in accordance with the principles of the Declaration of Helsinki.
This study is a prespecified subanalysis of the EARNEST-PVI trial focusing on the efficacy of the PVI-alone strategy in comparison with the extensive strategy for persistent AF with a trigger-based mechanism, with reference to a substrate-based mechanism. In this study, patients were stratified into 3 groups based on AF mechanisms: (1) substrate type; (2) PV trigger type; and (3) non-PV trigger type. We compared the efficacy of each strategy among these groups.
Study Participants
Patients were recruited from 8 experienced centers. Persistent AF was defined as a sustained episode lasting ≥7 days and <5 years at enrollment. The main inclusion criterion was a first-time ablation procedure for persistent AF. Exclusion criteria were as follows: an LA diameter ≥50 mm in a parasternal long-axis view on echocardiography; valvular AF; a history of cardiac surgery; dialysis; heart failure (left ventricular ejection fraction <30% and New York Heart Association classification III or IV); and age <20 or ≥80 years. The details have been previously described.5,6
Participants Subgroups
At the beginning of each procedure, an electrical cardioversion was performed to assess for PACs triggering AF from PV and non-PV origins. In cases where spontaneous AF initiation was not observed and sinus rhythm was maintained over a 5-min observation period, we performed an isoproterenol test consisting of a 0.1 µg/kg bolus followed by an initial infusion rate of 0.05 µg/kg/min, which doubled every 2 min to a maximum of 0.4 µg/kg/min. The criteria for discontinuing the isoproterenol test were: (1) 0.4 µg/kg/min administered for ≥5 min; (2) systolic blood pressure ≤80 mmHg; (3) heart rate ≥130 beats/min; and (4) detection of AF triggering. Because AF triggers would sometimes appear after isoproterenol interruption, we continued observation for 5 min after discontinuation of the infusion. AF triggers were defined as reproducible PACs initiating AF more than once. If AF triggers were not confirmed spontaneously or throughout the induction test, the patient was assigned to the substrate group. When the AF triggers were observed to originate from PVs only, the patient was assigned to the PV trigger group. If AF triggers from non-PV origins were confirmed, the patient was assigned to the non-PV trigger group, regardless of the presence or absence of any PV triggers.
Study Procedures
The protocol procedure included isolation of a circumferential area around both ipsilateral PVs with the verification of conduction block; however, an individual PVI was also acceptable. Procedures were performed by radiofrequency alone and the recommended energy setting was 25–35 W. The PVI was reconfirmed >20 min after the initial success of the PVI. Additional ablation, as recommended in the guidelines, including a non-PV AF trigger ablation plus ablation of clinical atrial flutter, paroxysmal supraventricular tachycardia, and common atrial flutter induced by burst pacing, were also allowed in both arms.6
Patients assigned to the additional ablation arm (PVI-plus group) subsequently underwent a CFAE ablation, linear ablation, or both, as decided by the physician. For the CFAE ablation, CFAE mapping was required during AF. The CFAE sites were identified by validated and automated algorithms of a 3-dimensional mapping system, as described by Dohi et al.6
The endpoint of the CFAE ablation was the elimination of all local CFAE sites or AF termination. AF termination was defined as a direct transition to sinus rhythm or to an organized atrial tachycardia or flutter. In cases undergoing linear ablation, ablation of 2 linear lesions was mandatory. The first had to be an anterior mitral line or posterior mitral isthmus line connecting the PV encircling lesion and the mitral annulus. The second had to be an ablation of lesions connecting the superior and/or inferior aspect of the encircling lesions for the PVI. The endpoint of the linear ablation was a complete, bidirectional block across the linear lesion. This bidirectional conduction block was rechecked at the end of the procedure or >20 min after the initial success of the conduction block. We allowed additional ablation procedures recommended by the guidelines, such as focal ablation for reproducible non-PV triggers; superior vena cava (SVC) isolation if SVC triggers were identified; ablation of clinical supraventricular tachycardias due to AV nodal reentry or an accessory pathway; and cavotricuspid isthmus linear ablation if patients had clinical or inducible typical atrial flutter in this study. The decision to stop additional radiofrequency energy applications for safety or for other reasons involving difficulties associated with eliminating all CFAEs or creating a complete conduction block despite the operator’s best efforts was left to the discretion of the operator.
Patient Follow-up
Patients were followed up at 1, 3, 6, 9, and 12 months after the initial ablation procedure. Each scheduled follow-up visit included an electrocardiogram (ECG) and medication assessment. A 24-h Holter ECG was acquired at 6 and 12 months. In addition to the scheduled follow up, the study participants had free access to health-care providers, including neighboring clinics and electrophysiology centers involved in this study. They were strongly recommended to visit a health-care provider if they felt symptoms that might be due to an arrhythmia or noticed any irregularity of their peripheral pulse on routine self-measurement. An ECG was performed at every additional visit, and cases with symptoms or findings suggestive of recurrence underwent Holter ECG monitoring and/or event monitor recording.
The blanking period was defined as the 3 months after the protocol therapy. Repeat ablation was allowed for patients with recurrence of AF, but was to be avoided during the blanking period. Repeat ablation during this period was counted as a recurrence just after the blanking period. Use of antiarrhythmic drugs during the blanking period was allowed, but discontinuation after the blanking period was strongly recommended.
Study Endpoints
The primary endpoint of the study was the recurrence of AF documented by scheduled or symptom-driven ECG tests during the 1-year follow-up period after the initial ablation procedure with or without antiarrhythmic drugs. Recurrence of AF was defined as the documentation by a 12-lead ECG or other appropriate tests for any atrial arrhythmia, including AF, atrial flutter, and/or atrial tachycardia lasting ≥30s. An independent events evaluation committee, whose members were unaware of any group allocation, adjudicated whether AF had recurred. Secondary endpoints included death from any cause, symptomatic stroke, periprocedural complications, total duration of energy application, and total energy delivery during the procedure.
Statistical Analysis
All analyses were performed using SPSS 26.0 (IBM Corporation, Armonk, NY, USA) or R software (version 4.0.3; R Foundation for Statistical Computing, Vienna, Austria). A P value <0.05 was considered statistically significant. The full analysis set (FAS) was defined as the set of all randomized patients that met all inclusion criteria and had undergone ablation procedures. This FAS population was used in the current analysis. Statistical evaluation in this study was all based on the intention-to-treat principle. All patients were randomly assigned to PVI-alone vs. PVI-plus ablation strategies in a 1 : 1 fashion. As described above, patients were stratified into 3 groups based on AF mechanisms: (1) substrate group; (2) PV trigger group; and (3) non-PV trigger group. The efficacy of each strategy was compared among the mechanism groups.
Data are presented with listwise deletion. Categorical variables are expressed as counts (percentages) and compared with the chi-squared test or Fisher’s exact test. Continuous variables are expressed as mean (standard deviation) or median (interquartile range) and compared using a Student’s t-tests or analysis of variance (ANOVA) and the Mann-Whitney U-tests or Kruskal-Wallis test, respectively. The primary endpoint was assessed according to ablation strategy within each type of AF mechanism in a time-to-first-event fashion with the Kaplan-Meier method and compared with the log-rank test. The effect of the ablation strategy on study endpoints was assessed with the Cox proportional hazards model. The presence of a statistically significant interaction between ablation strategy and AF mechanisms was tested by using the Wald test. An interaction term between ablation strategy and AF mechanism was included in the multivariable models to identify AF mechanism-related differences in the efficacy of ablation strategy. The proportional hazards assumption of ablation strategy for the primary endpoint was confirmed by using Schoenfeld residuals (P=0.770).
Results
Study Subjects
The EARNEST-PVI trial enrolled and randomized 512 patients (254 PVI-alone group vs. 258 PVI-plus group) (Figure 1). After excluding 1 patient whose trigger information was missing from the FAS population, a total of 496 patients were stratified according to AF mechanisms into substrate group (n=236), PV trigger group (n=236), and non-PV trigger group (n=24). Baseline characteristics were overall well balanced among the AF mechanism groups (Table 1). There were more female patients in the non-PV trigger groups than in the others. Ablation procedures also did not differ among the AF mechanism groups, with the exception of the use of Rhythmia, deflectable sheath, and performance of CFAE ablation (Table 2). Patients in the non-PV trigger group were more frequently prescribed with class I antiarrhythmic drugs both at hospital discharge and 12-month follow up (Supplementary Table).
Table 1.
Ablation Procedural Details
| |
Substrate group |
PV trigger group |
Non-PV trigger group |
P
value* |
PVI-alone
(N=108) |
PVI-plus
(N=128) |
PVI-alone
(N=122) |
PVI-plus
(N=114) |
PVI-alone
(N=18) |
PVI-plus
(N=6) |
| Age, years |
68.00
[61.50, 73.25] |
66.00
[57.00, 72.00] |
67.00
[59.00, 72.00] |
66.00
[59.00, 71.75] |
66.50
[60.25, 72.75] |
63.50
[57.75, 68.50] |
0.925 |
| Female sex |
30 (27.8) |
29 (22.7) |
23 (18.9) |
26 (22.8) |
9 (50.0) |
3 (50.0) |
0.006 |
| Height, cm |
166.85
[159.32, 172.00] |
166.45
[162.00, 171.10] |
165.75
[160.12, 170.88] |
167.00
[160.20, 173.00] |
163.75
[154.50, 170.12] |
163.10
[157.93, 167.30] |
0.267 |
| Body weight, kg |
68.05
[57.95, 74.00] |
67.30
[59.82, 74.93] |
67.30
[59.35, 75.00] |
67.15
[60.00, 74.97] |
65.50
[56.35, 72.95] |
62.80
[57.65, 65.85] |
0.404 |
| Family history of AF |
10 (9.3) |
9 (7.0) |
12 (9.8) |
6 (5.3) |
1 (5.6) |
0 (0.0) |
0.792 |
Long standing
persistent AF |
24 (22.2) |
36 (28.1) |
32 (26.2) |
27 (23.7) |
3 (16.7) |
2 (33.3) |
0.885 |
Duration of
persistent AF, days |
123.50
[61.25, 344.50] |
161.00
[86.75, 439.00] |
116.50
[56.75, 385.50] |
137.50
[74.25, 336.25] |
104.00
[58.25, 202.00] |
189.50
[97.75, 405.00] |
0.618 |
| History |
| Hypertension |
63 (58.3) |
83 (64.8) |
74 (60.7) |
64 (56.1) |
12 (66.7) |
2 (33.3) |
0.742 |
| Diabetes mellitus |
17 (15.7) |
22 (17.2) |
19 (15.6) |
24 (21.1) |
1 (5.6) |
1 (16.7) |
0.457 |
| Dyslipidemia |
45 (41.7) |
60 (46.9) |
60 (49.2) |
53 (46.5) |
6 (33.3) |
2 (33.3) |
0.356 |
| CHF |
21 (19.4) |
24 (18.8) |
19 (15.6) |
22 (19.3) |
5 (27.8) |
0 (0.0) |
0.848 |
| MI |
1 (0.9) |
3 (2.3) |
3 (2.5) |
6 (5.3) |
0 (0.0) |
0 (0.0) |
0.252 |
| PCI |
3 (2.8) |
5 (3.9) |
5 (4.1) |
9 (7.9) |
1 (5.6) |
0 (0.0) |
0.419 |
| PVD |
2 (1.9) |
3 (2.3) |
2 (1.6) |
1 (0.9) |
1 (5.6) |
0 (0.0) |
0.533 |
| SSS |
1 (0.9) |
3 (2.3) |
1 (0.8) |
1 (0.9) |
1 (5.6) |
0 (0.0) |
0.371 |
| Stroke |
7 (6.5) |
13 (10.2) |
6 (4.9) |
10 (8.8) |
3 (16.7) |
0 (0.0) |
0.544 |
| SAS |
8 (7.4) |
13 (10.2) |
13 (10.7) |
17 (14.9) |
2 (11.1) |
0 (0.0) |
0.378 |
| Thyroid disease |
3 (2.8) |
9 (7.0) |
4 (3.3) |
5 (4.4) |
2 (11.1) |
0 (0.0) |
0.546 |
| COPD |
2 (1.9) |
4 (3.1) |
10 (8.2) |
4 (3.5) |
2 (11.1) |
0 (0.0) |
0.129 |
| CKD |
5 (4.6) |
5 (3.9) |
6 (4.9) |
7 (6.1) |
2 (11.1) |
0 (0.0) |
0.616 |
| Liver dysfunction |
9 (8.3) |
4 (3.1) |
7 (5.7) |
8 (7.0) |
0 (0.0) |
0 (0.0) |
0.434 |
| Data on hospital admission |
| Hemoglobin, g/dL |
14.80
[13.50, 15.40] |
14.60
[13.90, 15.20] |
14.75
[13.93, 15.78] |
14.30
[13.43, 15.10] |
13.85
[12.77, 15.45] |
13.90
[12.28, 15.83] |
0.389 |
| BNP, pg/mL |
151.10
[102.00, 223.00] |
144.35
[91.35, 221.25] |
133.75
[84.53, 203.18] |
149.85
[106.80, 216.22] |
138.05
[116.68, 259.33] |
176.50
[82.10, 279.60] |
0.889 |
| Creatinine, mg/dL |
0.90
[0.77, 1.00] |
0.88
[0.77, 1.00] |
0.85
[0.79, 0.99] |
0.90
[0.82, 1.00] |
0.88
[0.68, 0.98] |
0.81
[0.76, 0.90] |
0.242 |
| CRP, mg/dL |
0.10
[0.05, 0.16] |
0.10
[0.06, 0.15] |
0.10
[0.07, 0.21] |
0.10
[0.06, 0.20] |
0.08
[0.05, 0.10] |
0.09
[0.06, 0.14] |
0.042 |
| LA diameter, mm |
41.00
[39.00, 45.00] |
42.00
[39.00, 45.00] |
43.00
[39.00, 46.00] |
43.00
[39.12, 46.00] |
42.50
[40.00, 46.75] |
45.50
[35.25, 49.00] |
0.113 |
Data are expressed as median [interquartile range] or number (percentage). *P values for comparisons between different AF mechanisms (substrate vs. PV trigger vs. non-PV trigger). AF, atrial fibrillation; BNP, brain natriuretic peptide; CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; LA, left atrial; MI, myocardial infarction; PCI, percutaneous coronary intervention; PV, pulmonary vein; PVD, peripheral vascular disease; PVI, pulmonary vein isolation; SAS, sleep apnea syndrome; SSS, sick sinus syndrome.
Table 2.
Procedural Details
| |
Substrate group |
PV trigger group |
Non-PV trigger group |
P
value* |
PVI-alone
(N=108) |
PVI-plus
(N=128) |
PVI-alone
(N=122) |
PVI-plus
(N=114) |
PVI-alone
(N=18) |
PVI-plus
(N=6) |
| Three-dimensional mapping system |
| CARTO |
101 (93.5) |
117 (91.4) |
113 (92.6) |
104 (91.2) |
18 (100.0) |
6 (100.0) |
0.356 |
| EnSite |
4 (3.7) |
5 (3.9) |
9 (7.4) |
9 (7.9) |
0 (0.0) |
0 (0.0) |
0.091 |
| Rhythmia |
3 (2.8) |
7 (5.5) |
0 (0.0) |
1 (0.9) |
0 (0.0) |
0 (0.0) |
0.014 |
| Deflectable sheath |
32 (29.6) |
55 (43.0) |
57 (46.7) |
60 (52.6) |
6 (33.3) |
3 (50.0) |
0.018 |
Contact force sensing
catheter |
100 (92.6) |
113 (88.3) |
114 (93.4) |
110 (96.5) |
17 (94.4) |
6 (100.0) |
0.125 |
| CFAE ablation |
0 (0.0) |
25 (19.5) |
0 (0.0) |
13 (11.4) |
0 (0.0) |
0 (0.0) |
0.041 |
| Linear ablation |
0 (0.0) |
104 (81.2) |
0 (0.0) |
101 (88.6) |
0 (0.0) |
6 (100.0) |
0.197 |
| LA roof |
0 (NA) |
103 (99.0) |
0 (NA) |
101 (100.0) |
0 (NA) |
6 (100.0) |
0.596 |
| Unsuccessful block |
0 (NA) |
4 (3.9) |
0 (NA) |
3 (3.0) |
0 (NA) |
0 (0.0) |
0.842 |
| LA bottom |
0 (NA) |
53 (51.0) |
0 (NA) |
53 (52.5) |
0 (NA) |
4 (66.7) |
0.752 |
| Unsuccessful block |
0 (NA) |
3 (5.7) |
0 (NA) |
3 (5.7) |
0 (NA) |
0 (0.0) |
0.887 |
| LA anterior wall |
0 (NA) |
21 (20.2) |
0 (NA) |
19 (18.8) |
0 (NA) |
0 (0.0) |
0.470 |
| Unsuccessful block |
0 (NA) |
2 (9.5) |
0 (NA) |
4 (21.1) |
0 (NA) |
0 (NA) |
NA |
| Mitral isthmus |
0 (NA) |
81 (77.9) |
0 (NA) |
84 (83.2) |
0 (NA) |
6 (100.0) |
0.305 |
| Unsuccessful block |
0 (NA) |
20 (24.7) |
0 (NA) |
22 (26.2) |
0 (NA) |
0 (0.0) |
0.354 |
Ganglionated plexus
ablation |
0 (0.0) |
1 (0.8) |
0 (0.0) |
1 (0.9) |
0 (0.0) |
0 (0.0) |
0.950 |
| SVC isolation |
4 (3.7) |
2 (1.6) |
1 (0.8) |
4 (3.5) |
2 (11.1) |
0 (0.0) |
0.191 |
| Unsuccessful block |
0 (0.0) |
1 (50.0) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0 (NA) |
0.532 |
| CTI ablation |
31 (28.7) |
41 (32.0) |
34 (27.9) |
32 (28.1) |
2 (11.1) |
1 (16.7) |
0.172 |
| Unsuccessful block |
1 (3.2) |
1 (2.4) |
0 (0.0) |
1 (3.1) |
0 (0.0) |
0 (0.0) |
0.848 |
| Procedure time, min |
140.00
[109.75, 175.00] |
180.00
[126.25, 245.00] |
145.00
[112.00, 170.00] |
180.00
[141.25, 220.75] |
161.50
[131.75, 194.00] |
197.50
[195.00, 200.00] |
0.520 |
Data are expressed as median [interquartile range] or number (percentage). *P values for comparisons between different AF mechanisms (substrate vs. PV trigger vs. non-PV trigger). CFAE, complex fractionated atrial electrogram; CTI, cavo tricuspid isthmus; NA, not applicable; SVC, superior vena cava. Other abbreviations as in Table 1.
The event rate of the primary endpoint of AF recurrence at 1 year was numerically higher with PVI-alone than with PVI-plus in both substrate groups (28.7% vs. 20.3%, log-rank P=0.155) and the PV trigger group (29.5% vs. 19.3%, log-rank P=0.062), although it did not reach a statistical significance (Figure 2). In the non-PV trigger group, there was no difference between both ablation strategies (50% vs. 50%, log-rank P=0.923). The hazard ratios for the primary endpoint of the PVI-alone strategy compared to the PVI-plus strategy were 1.456 (95% confidence interval (CI) 0.864–2.452) in the substrate group, 1.648 (95% CI 0.969–2.801) in the PV trigger group, and 0.937 (95% CI 0.252–3.488) in the non-PV trigger group. No significant interaction between ablation strategy and mechanism types was observed (P value for interaction=0.748) (Figure 3).
Secondary Endpoints
Secondary endpoints are summarized in
Table 3. Death from any cause and symptomatic stroke occurred in 1 and 3 patients at 1 year, respectively. Procedural complications, total duration of energy application, and total energy delivery during the index procedure did not differ among the different AF mechanism types.
Table 3.
Secondary Endpoints
| |
Substrate group |
PV trigger group |
Non-PV trigger group |
P value* |
PVI-alone
(N=108) |
PVI-plus
(N=128) |
PVI-alone
(N=122) |
PVI-plus
(N=114) |
PVI-alone
(N=18) |
PVI-plus
(N=6) |
| Death from any cause |
0 (0.0) |
1 (0.8) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0.576 |
| Symptomatic stroke |
1 (0.9) |
1 (0.8) |
1 (0.8) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0.777 |
| Complications during the index procedure |
1 (0.9) |
3 (2.3) |
3 (2.5) |
6 (5.3) |
1 (5.6) |
0 (0.0) |
0.350 |
| Hematoma |
0 (0.0) |
1 (0.8) |
1 (0.8) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0.950 |
| Systemic embolism |
0 (0.0) |
0 (0.0) |
0 (0.0) |
1 (0.9) |
0 (0.0) |
0 (0.0) |
0.576 |
| Pericarditis |
0 (0.0) |
0 (0.0) |
0 (0.0) |
1 (0.9) |
0 (0.0) |
0 (0.0) |
0.576 |
| Cardiac tamponade |
0 (0.0) |
1 (0.8) |
0 (0.0) |
1 (0.9) |
0 (0.0) |
0 (0.0) |
0.950 |
| Atrioventricular block |
0 (0.0) |
0 (0.0) |
1 (0.8) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0.576 |
| Infection |
1 (0.9) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0.576 |
| Heart failure |
0 (0.0) |
1 (0.8) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0.576 |
| Esophageal vagal nerve injury |
0 (0.0) |
0 (0.0) |
1 (0.8) |
3 (2.6) |
1 (5.6) |
0 (0.0) |
0.052 |
Total duration of energy application
during the index procedure, s |
1,803.50
[1,389.75,
2,349.50] |
2,882.00
[2,029.00,
3,784.00] |
1,919.00
[1,457.00,
2,513.00] |
2,880.00
[2,374.00,
3,539.25] |
2,014.00
[1,623.00,
2,376.00] |
3,300.00
[2,652.50,
3,557.50] |
0.860 |
Total energy delivery during the index
procedure, J |
55,754.00
[41,671.50,
76,627.50] |
84,246.50
[61,921.50,
124,160.50] |
56,740.00
[43,985.00,
81,961.00] |
90,234.50
[68,602.50,
114,185.50] |
55,822.00
[41,861.25,
76,001.25] |
109,730.00
[109,553.00,
117,612.00] |
0.932 |
Data are expressed as median [interquartile range] or number (percentage). *P values for comparisons between different AF mechanisms (substrate vs. PV trigger vs. non-PV trigger). Abbreviations as in Table 1.
Distributions of the origins of reproducible PV trigger (PACs) in the PV-trigger group are shown in
Table 4. Two-thirds of the patients had PACs originating from the left PVs, whereas half of the patients had those originating from the right PVs. Both in the left and right PVs, the majority of the triggers originated from the superior PVs. Origins of non-PV trigger in the non-PV trigger group are summarized in
Table 5. The most frequent origin was the right atrial septum, followed by the high right atrium and left atrial posterior wall. In the non-PV trigger group, the success rate of non-PV trigger ablation was higher in the PVI-alone arm than in the PVI-plus arm. However, the primary endpoint of AF recurrence similarly occurred between both ablation strategies in the non-PV trigger group (Figure 2).
Table 4.
Origins of Premature Atrial Contractions (Triggers) in the PV Trigger Group
| |
PVI-alone
(N=122) |
PVI-plus
(N=114) |
| Left PV |
86 (70.5) |
74 (64.9) |
| Left superior PV |
71 (82.6) |
56 (75.7) |
| Left inferior PV |
14 (16.3) |
13 (17.6) |
| Left PV (superior or inferior undetermined) |
7 (8.1) |
8 (10.8) |
| Right PV |
63 (51.6) |
59 (51.8) |
| Right superior PV |
56 (88.9) |
49 (83.1) |
| Right inferior PV |
4 (6.3) |
7 (11.9) |
| Right PV (superior or inferior undetermined) |
3 (4.8) |
5 (8.5) |
Data are expressed as number (percentage). PV, pulmonary vein; PVI, pulmonary vein isolation.
Table 5.
Origins of Premature Atrial Contractions (Triggers) in the Non-PV Trigger Group
| |
PVI-alone
(N=18) |
PVI-plus
(N=6) |
| Number of non-PV triggers |
1.00 [1.00, 2.00] |
2.00 [1.25, 2.00] |
| High right atrium |
4 (22.2) |
1 (16.7) |
| Right atrial lateral wall |
2 (11.1) |
0 (0.0) |
| Right atrial septum |
3 (16.7) |
3 (50.0) |
| LA anterior wall |
1 (5.6) |
0 (0.0) |
| LA lateral wall |
0 (0.0) |
1 (16.7) |
| LA posterior wall |
4 (22.2) |
1 (16.7) |
| LA septum |
3 (16.7) |
0 (0.0) |
| Superior vena cava |
3 (16.7) |
1 (16.7) |
| Coronary sinus |
1 (5.6) |
2 (33.3) |
| Mitral valve |
1 (5.6) |
0 (0.0) |
| Unknown |
5 (27.8) |
2 (33.3) |
| Ablation unsuccessful |
13/27 (48.1) |
8/11 (72.7) |
Data are expressed as median [interquartile range] or number (percentage). Abbreviations as in Table 1.
Discussion
In this pre-specified subanalysis of the EARNEST-PVI trials, our predefined hypothesis that a PVI-alone strategy is sufficient to maintain sinus rhythm in PV trigger-based persistent AF was rejected. The superiority of the PVI-plus strategy over the PVI-alone strategy was consistent across substrate-based and trigger-based persistent AF, although it did not reach the statistical significance due to the underpowered sample size.
PVI is a cornerstone not only for paroxysmal AF, but also for persistent AF. However, because patients with persistent AF are assumed to have advanced non-PV arrhythmogenic substrates, intervention with extensive ablation in addition to PVI might be desirable to obtain better clinical outcome. Several randomized controlled trials have been conducted to investigate the efficacy of empiric extensive intervention with linear and CFAE ablation over the PVI-alone strategy,1–3
but they have consistently failed to demonstrate the efficacy of the routine addition of CFAE ablation or linear ablation in comparison with PVI alone. Based on these previous findings, we conducted the EARNEST-PVI trial to assess the non-inferiority of the PVI-alone strategy compared with the PVI-plus strategy. However, the EARNEST-PVI trial failed to establish the non-inferiority of the PVI-alone strategy, instead showing the possible superiority of the extensive ablation strategy.5
The heterogeneity of the current evidence might be attributed to the heterogeneity of the pathophysiology of AF. An individualized approach based on the pathophysiology of the development and persistence of AF in each patient is desirable, but there are currently no established methods to address this.
“Triggers” are important for the initiation of AF, whereas “substrates” are necessary for the maintenance of persistent AF. The dominant player for AF persistence could vary in different cases. Based on the dominance of AF persistence mechanisms, we previously proposed that mechanisms of AF persistence might be classified into a substrate-based type and a trigger-based type.7
In the trigger-based mechanism, the activity of the AF triggers (PACs) is so elevated that AF is initiated frequently, and a “new” AF occurs before the “old” one terminates and, as a result, AF persists. If the persistent AF patients with this trigger-based mechanism of AF received electric cardioversion, AF would recur immediately (immediate recurrence of AF: IRAF). The other type of persistent AF can be classified as the substrate-based mechanism.
We hypothesized that in patients with reproducible AF triggered by PACs originating only from PVs, PVI alone would be enough to maintain sinus rhythm. This study, however, unexpectedly rejected this hypothesis. There are several possible explanations. First, the methodology for subclassification of AF persistence mechanisms might be insufficient. In this study, reproducibility of AF initiation by PAC triggers was checked at the beginning of the ablation procedure. Patients in the PV-trigger groups had reproducible initiation of AF by PACs from PVs. However, non-PV substrates may also play an important role in cases in the PV trigger group as well as in the substrate group. In addition, undetected non-PV triggers might have existed in a substantial portion of the patients in the PV trigger group. As shown in
Table 1, baseline characteristics did not differ among the AF mechanism groups, except for more frequent female gender in the non-PV trigger group, as reported previously.8
Comorbidities such as hypertension, diabetes, dyslipidemia, and obesity are associated with progression of AF substrates.9–14
Left atrial diameter as a geometrical parameter did not differ as well. These points suggest similar progression of non-PV AF triggers and substrates both in the trigger-based and substrate-based mechanism groups. Because our methodology appeared insufficient to subclassify the patients, a better classification methodology needs to be established. Second, the procedural quality, namely, the durability of PVI, may have strongly influenced the results of the trial. Non-durable PVI may readily result in PV reconnection and thus lead to AF recurrence, especially in the PV-trigger group. Though the PV acute reconnection rate was similar between the groups (PVI-alone vs. PVI-plus, 64.3% vs. 65.5%),5
longer procedure time in the PVI-plus arm might partially contribute to a higher possibility to recognize PV acute reconnections, which presumably resulted in more durable PVI. Third, as mentioned above, possible heterogeneity of AF mechanisms may have led to the heterogeneous findings in the current evidences. The mean age in the previous randomized trials conducted in the US and Europe was 58–63 years, whereas in our study, the mean age was 65±9 years.1–3
The older population in our trial may simply suggest the existence of greater progression of arrhythmogenic substrates than in the populations in the previous trials. The superiority of the PVI-plus strategy in the current population might be attributed to this point. However, the current persistent AF population had a relatively short duration of AF persistence (median 138, interquartile range [66, 364] days), which suggests mild progression of non-PV arrhythmogenicity.15
Therefore, the PVI-alone strategy might have been unexpectedly effective in the substrate group, which in turn has concealed the relative effectiveness of this strategy in the PV trigger group.
Clinical Implications
Consistent superiority of the PVI-plus strategy over the PVI-alone strategy was observed, although this study is underpowered to draw a robust conclusion. Nevertheless, the findings would not justify a larger-scale study to establish the sufficiency of the PVI-alone strategy in patients with a PV trigger, because of the consistent trend of efficacy provided by the extensive strategy in the different AF mechanism types. This suggests that the extensive ablation is effective in some patients with persistent AF irrespective of whether its mechanism is trigger-based or substrate-based. Even in cases that showed reproducible initiation of AF triggered by PACs exclusively from PVs, the PVI-plus strategy should be considered as an important option. An electrophysiology study with electrical cardioversion at the beginning of an AF ablation procedure to identify patients with PV triggers would not be useful in the clinical setting. An individualized, tailor-made approach according to the pathophysiology of AF would still be desirable, but the methodology to assess the AF mechanisms in this study seems to be insufficient. We need to establish an appropriate methodology for classifying AF mechanisms. In addition to background characteristics and electrophysiology studies, computed tomography and cardiac magnetic resonance imaging might also be candidates as assessment tools.16–19
Future investigations with a novel stratification methodology to identify the dominant AF mechanisms in each case are required to establish a systematic tailor-made approach for persistent AF.
Study Limitations
Several limitations should be acknowledged. First, although the present study is a prespecified subanalysis of a prospective randomized controlled trial, the sample size was under-powered to detect a difference between PVI-alone and PVI-plus strategies in each AF mechanism group. Second, the primary endpoint of recurrence of AF might have been underreported in both groups. In this study, the participants had ECG tests at every visit and free access to health-care providers. However, an implantable loop recorder would be desirable. Third, the longer procedure time in the PVI-plus arm may partially contribute to the more durable PVI than that in the PVI-alone arm, as we described above. Finally, this study was conducted mainly in an East Asian population. Generalizability of the findings to other populations should be carefully considered.
Conclusions
This prespecified subanalysis of the EARNEST-PVI trial indicated that the efficacy of the PVI-plus strategy compared with the PVI-alone strategy was consistent across trigger-based and substrate-based persistent AF. The PVI-plus strategy should be considered even in cases that had AF triggers exclusively from PVs. Future investigations with a novel stratification method to identify dominant AF mechanisms in each case are required to establish a systematic tailor-made approach for persistent AF.
Acknowledgement
The authors thank the members of the OCVC-Arrhythmia Investigators and staff and participants of the EARNEST-PVI trial. A full list of staff, investigators, and institutions can be found in the
Appendix.
Disclosures
K.I. has received personal fees from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, and Medtronic, outside the submitted work. Y. Sotomi has received research grants and personal fees from Abbott Vascular Japan, Boston Scientific Japan, TERUMO, Japan Lifeline, Biosensors, Medtronic, Daiichi-Sankyo, Bayer, Boehringer Ingelheim, and Bristol-Myers Squibb outside the submitted work, and is an endowed chair funded by TERUMO, Asahi Intecc, NIPRO, and Shimadzu Corporation; M. Masuda has received personal fees from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, Boston Scientific, Abbott, Nihon Kohden, Otsuka Pharmaceutical, AstraZeneca, and Medtronic, outside the submitted work; Y.F. has received personal fees from Biosense Webster, Abbott, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, Bayer, Daiichi Sankyo, Nihon Kohden, and Fukuda Denshi, outside the submitted work; A.H. has received personal fees from Boehringer Ingelheim, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Toa Eiyo, Medtronic, Biotronik, Ono Pharmaceutical, Takeda Pharmaceutical, Pfizer, and Abbott, outside the submitted work; Y.E. has received personal fees from Japan Lifeline and Medtronic, and non-financial support from Johnson & Johnson, Abbott, and Medtronic, outside the submitted work; T.W. has received personal fees from Biosense Webster, Abbott, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, Bayer, Daiichi Sankyo, Nihon Kohden, and Fukuda Denshi, outside the submitted work; H. Minamiguchi has received grants from Medtronic, Johnson & Johnson, and Abbott, during the conduct of the study; personal fees from Medtronic, Abbott, Johnson & Johnson, Nihon Kohden, Biotronik, Japan Lifeline, Daiichi Sankyo, Bayer, Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Kowa, Ono Pharmaceutical, and Otsuka Pharmaceutical, outside the submitted work; N.T. has received personal fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, Medtronic, and Philips outside the submitted work; T.O. has received personal fees from Medtronic, Biotronik, Abbott, Daiichi Sankyo, Beyer, Bristol-Myers Squibb, Boehringer Ingelheim, MSD, and AstraZeneca, outside the submitted work; T.K. has received personal fees from Boehringer Ingelheim, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Nihon Kohden, Abbott, Medtronic, and Otsuka Pharmaceutical, outside the submitted work; Y.M. has received personal fees from Daiichi Sankyo, Toa Eiyo, Medtronic, and Biotronik, outside the submitted work. M.K. has received personal fees from Medtronic, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Bristol-Myers Squibb, and Abbott, and grants from Osaka Heart Club, outside the submitted work; T.D. has received grants from Medtronic, Johnson & Johnson, and Abbott, during the study; A.S. has received grants from Medtronic, Johnson & Johnson, and Abbott, during the study; and personal fees from Bayer, Daiichi Sankyo, and Medtronic, outside the submitted work; H. Mizuno has received grants from Medtronic, Johnson & Johnson, and Abbott, during the study; personal fees from Daiichi Sankyo, Bayer, Japan Lifeline, Boehringer Ingelheim, Toa Eiyo, Pfizer, and Medtronic; endowed chair lecturer funded by Terumo, outside the submitted work; D.N. has received grants from Medtronic, Johnson & Johnson, and Abbott, during the study; grants from Daiichi Sankyo, outside the submitted work; S.H. has received grants from Medtronic, Johnson & Johnson, and Abbott, during the study; personal fees from Bayer, Daiichi Sankyo, Medtronic, Boehringer Ingelheim, Johnson & Johnson, Roche Diagnostics, Fujifilm Toyama Chemical, and Actelion; and non-financial support from Actelion, outside the submitted work; Y. Sakata has received grants from Medtronic, Johnson & Johnson, and Abbott, during the conduct of the study; personal fees from Abbott, Sanofi, Johnson & Johnson, Daiichi Sankyo, Terumo, Medtronic, Bayer, Biotronik, Bristol-Myers Squibb, Boehringer Ingelheim, and Boston Scientific, outside the submitted work; M. Miyoshi, M.O., and T.K. have nothing to disclose. This study was funded by Medtronic, Johnson & Johnson, and Abbott.
Y. Sakata is an Editorial Board member for
Circulation Journal.
IRB Information
The following institutes approved this study: Cardiovascular Center, Sakurabashi-Watanabe Hospital (study number: 17-6); Osaka University Graduate School of Medicine (14377); Kansai Rosai Hospital (15D059 g); Osaka General Medical Center (27-2035); Osaka Police Hospital (548); Osaka Rosai Hospital (28-78); Yao Municipal Hospital: (八病H29-5); and Osaka Hospital, Japan Community Healthcare Organization (2016-25).
Data Availability
The data underlying this article will be shared upon reasonable request up to 1 year after publication. The data contain the baseline and follow-up data of patients in Japanese, the study protocol in Japanese, and the statistical analysis plan in Japanese. Requests should be made to the corresponding author. The proposal may be reviewed for approval by the responsible personnel at the OCVC-Arrhythmia Investigators. The data are applicable only for analyses of our study findings. The data will be shared in an appropriate way to meet the type of data ordered.
Appendix. The OCVC-Arrhythmia Investigators
Chair
Yasushi Sakata, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita 565-0871, Japan.
Secretariat
Shungo Hikoso (Chief), Daisaku Nakatani, Hiroya Mizuno, Shinichiro Suna, Katsuki Okada, Tomoharu Dohi, Yohei Sotomi, Akihiro Sunaga, Hirota Kida, Bolrathanak Oeun, and Taiki Sato; Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
Investigators (institutions are listed in alphabetical order)
Shinji Hasegawa and Miwa Miyoshi: Osaka Hospital, Japan Community Healthcare Organization Osaka, Japan; Toshiaki Mano, Masaharu Masuda, Takashi Kanda, Yasuhiro Matsuda: Kansai Rosai Hospital, Amagasaki, Japan; Masatake Fukunami, Takahisa Yamada, Tetsuya Watanabe, Yoshio Furukawa, and Masato Kawasaki: Osaka General Medical Center, Osaka, Japan; Yoshiharu Higuchi, Nobuhiko Makino, Hitoshi Minamiguchi, and Akio Hirata: Osaka Police Hospital, Osaka, Japan; Jun Tanouchi, Masami Nishino, Yasuharu Matsunaga, and Yasuyuki Egami: Osaka Rosai Hospital, Sakai, Japan; Yasushi Sakata, Yasushi Matsumura, Shungo Hikoso, Daisaku Nakatani, Hiroya Mizuno, Toshihiro Takeda, Takafumi Oka, Tomoaki Nakano, and Kentaro Ozu: Osaka University Graduate School of Medicine, Suita, Japan; Koichi Inoue, Koji Tanaka, and Nobuaki Tanaka: Sakurabashi Watanabe Hospital, Osaka, Japan; and Tomoko Minamisaka and Shiro Hoshida: Yao Municipal Hospital, Yao, Japan.
Supplementary Files
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-21-0126
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