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국문

지속성 심방 세동 (persistent atrial fibrillation, PeAF) 치료에 있어 냉각 풍선절제술 (cryoballoon catheter ablation ,CB)은 전극도자절제술 (radiofrequency ablation, RF)를 대체하는 수단으로 자리잡고 있다.1 발작성 심방세동 (paroxysmal atrial fibrillation, PAF) 에서 CB의 유효성 및 안전성은 최근 FIRE and ICE trial에서 잘 증명되었다. 2 시술시간이 짧고, 연속적인 병변을 만들 수 있으며, 쉽게 배울 수 있다는 점 등이 RF에 비해 CB가 가지는 장점이다. 2-4 그러나 이러한 CB의 유효성과 안전성은 PAF만 국한되어 있으며 PeAF 에 대한 결과는 아직 잘 알려져 있지않다. 
PeAF는 PAF와는 병태생리적인면에서 많은 차이가 있다. PAF는 대부분 폐정맥 (pulmonary vein, PV) 에서 나오는 유발점(trigger)에서 발생한다고 알려져 있다. 반면에 PeAF는 좌심방의 광범위한 재형성 (remodelling) 되면서 이 부위에서 발생하는 국소적 또는 회귀적 (reentrant) 기전들에 의해 부정맥이 유지된다.5 그래서 PV를 주 타겟으로 하는 CB는 PeAF에서는 제한적인 효과만 있을 가능성이 있다. 그러나 STAR-AF II trial 에서는 PV isolation에 더한 추가적인 선형절제술(linear ablation)이나 복잡전기신호 (CFAE, complex fractionated electrogram ablation) 절제술은 심방세동 절제술 후 예후를 향상시키지 못했다.6 이 연구는 심방세동에서 PV의 중요성을 다시 한 번 환기시킴과 함께CB를 통한 PV isolation 이 PeAF에서도 효과가 있을 가능성을 제시하였다. 최근에는 광범위한 폐정맥 주위 절제술 (wide antral ablation)이나 심방 후벽 절제술 (posterior wall isolation) 등의 확장된 CB 시술 (CB+) 등이 PeAF에서 좋은 효과를 보인다는 보고들이 알려지고 있다.7-9 따라서 PeAF에서 CB 또는 CB+ 에 대한 시도가 대규모 센터들에서 널리 시행되고 있다. 그러나 아직까지 PeAF에서 CB또는 CB+와 RF에 대한 무작위 배정 시험은 매우 부족한 실정이다 (Cryoballon Versus Radiofrequency Ablation for Persistent Atrial Fibrillation: IRON-ICE, NCT03365700, and FIRE and ICE 2 trial pilot, NCT03706677). 8-10 현재까지의 후향적 데이터들을 보면 PeAF 환자에서 표준치료인 RF에 비교한 CB 또는 CB+ 치료는 RF에 비해 더 좋은 결과를 보인다는 후향적 연구 결과들이 충분히 존재하고 있다. 특히 CB+는 CB에 비해서도 더 우월한 결과를 보일 가능성이 제시되고 있다. 또한 일반적으로 CB 및 CB+ 시술 방법은 RF 연구들에 비해 훨씬 안전하고 빠른 시술이 가능하여 보다 효과적이면서도 안전한 치료방법이 될 가능성이 충분히 있다. 이렇게 PeAF에서 CB+가 CB 또는 RF에 비교한 효과를 알기 위해서는 세 군을 모두 포함하는 무작위 배정연구가 필수적이다. 이를 통해서 CB+가 RF에 대한 우월성을 증명함과 동시에 Cryoballoon를 이용한 시술이 가장 효과적일 수 있는 시술 범위를 결정할 수 있을 것이다. 아직까지 세가지 치료법을 동시에 비교한 연구는 보고된 바가 없는 실정이다. 본 연구에서 우리는 CB+ 가 CB 또는 RF 보다 더 효과적이라는 가설을 세우고 이를 확인하기 위해 본 연구를 기획하였다.

영문

The cryoballoon catheter ablation (CB) for atrial fibrillation (AF) has evolved over the last several decades, and has become a reasonable alternative to radiofrequency (RF) pulmonary vein isolation (PVI).1 The efficacy of CB procedure in paroxysmal AF has been proven in the recent FIRE and ICE trial, where CB was non-inferior to RF ablation with respect to efficacy on AF free survival, but with no significant difference in overall safety.2 Shorter procedure/fluoroscopy time for contiguous transmural lesion, shorter learning curve, and higher quality of life would be major benefits of CB over RF ablation.2-4 However, this efficacy and safety of CB procedure has been proven only in patients with paroxysmal AF, and the role of CB in persistent AF remains largely unknown. 
Persistent AF has been known to be fundamentally different from paroxysmal AF.  Paroxysmal AF occurs primarily from the PV triggers while persistent AF is perpetuated by focal/reentrant mechanism in the process of atrial structural remodeling.5 Therefore, application of CB, due to its main effect on the PVs, has been regarded to provide only a limited effect in patients with persistent AF . However, the STAR-AF II trial demonstrated that substrate modification in addition to PVI either via linear ablation or via complex fractionated electrogram ablation do not result in reduction of AF recurrences in patients with persistent AF.6 This landmark study has provided a renewed insight into the role of PV in AF, and possible clinical application of CB in persistent AF patients. Furthermore, improved outcomes with extended CB procedures (CB plus) such as wide antral ablation, posterior wall isolation, or roof/perimitral linear lesionss have also suggested that CB could be applied in substrate modification in more advanced forms of AF.7-9 The use of CB in patients with persistent AF is rapidly growing in the current electrophysiology practice, and the new concept of extended CB ablation (CB plus) is being actively tested in selected large volume centers. In spite of the widespread use of CB, a direct comparison of RF vs CB in persistent AF in a prospective randomized way has been performed in one published10 and two ongoing studies (Cryoballon Versus Radiofrequency Ablation for Persistent Atrial Fibrillation: IRON-ICE, NCT03365700, and FIRE and ICE 2 trial pilot, NCT03706677). Comparison of CB vs CB plus has been performed in only two retrospective observational studies.8, 9 The review of previous observational data showed that CB or CB plus are potentially associated with better effectiveness than RF. Especially CB plus could be a better treatment option than CB in terms of prevention of recurrent AF/AFL. Besides, considering general advantage of CB or CB plus such as shorter procedure time and higher safety, CB+ could be a better treatment option than traditional RF. To better understand the role of CB in the management of persistent AF, and to measure the additional effect of extended CB ablation as opposed to CB alone, a trial comparing all the three arms is necessary. From this trial we could demonstrate the higher efficacy of CB plus compared to RF and optimal extent of CB ablation in persistent AF. To the best of our knowledge, clinical trials that directly compare the efficacy and safety of the three treatment options (RFCA, CB, and CB plus) at the same time have not been reported. In the current study, we hypothesized that the CB plus procedure would be more effective than CB or RF in the management of patients with persistent AF.

국문

- 무작위 배정은 인터넷을 기반으로 한 랜덤화 도구를 사용하여 365일 24시간 가능할 것이다. 
- 기본적으로 시술은 Trans-septal approach를 통해 좌심방 내에서 이루어진다. 
- Transseptal access 전후 헤파린을 사용하여 ACT 값이 300 이상 되도록 한다. 
- 시술전 CT 영상이 모든 환자에서 시행될 것이다. 
- 모든 환자들에서 절제술 시행후 PV potential 들을 체크하여 Entrance and exit blockd르 확인할 것이다. 
- 모든 경우 PV isolation이 표준 치료 로서 시행될 것이다. RF 군에서 추가적인 선형 절제술이나 CFAE 절제술 또는 CB 군에서 좌심방 후벽 절제술 시행은 반복적인 심방 빈맥이나 심방세동이 발생하지 않는 한 최대한 지양하고 PV isolation만 시행하도록 할 것이다. 
- CB+ 군에서는 좌심방 천자아에 대한 선형절제술 또는 좌심방 후벽 절제술이 시행되어야 한다 
- 모든 군에서 우심방 협부에서 발생하는 전형적 심방조동 (Cavo-tricuspid isthmus dependent flutter) 발생시에는 추가적인 RF 카테터 절제술을 시행할 수 있다. 
- 위의 시술 들에도 심방성 부정맥이 지속될 경우 직류 동율동 전환술을 시행한다. 
- 시술 후에는 Inducibility test가 시행될 수 있으며 이때는 isoproterenol (up to 10 mcg/min) 과 rapid atrial pacing (up to 180ms or atrial ERP) 을 이용하여 PV 외부의 유발점이 있는지를 살펴보고, 심방세동 발생 가능성을 알아본다.18-21 Inducibility 펴가는 환자 컨디션이나 시술 의사의 판단에 따라 변경될 수 있으며 1분이상 지속되는 심방성 빈맥이 있을 경우 유발 가능한 상태인 것으로 판단한다. 
-  PV 외부의 유발점이 isoproterenol 사용 중 반복적으로 발생할 경우 이에 대한 추가적인 절제술을 시행할 수 있다.

영문

- Randomization is carried out through an internet-based randomization system, available 24 hours per day, 7 days per week, 365 days per year
- All procedures will be performed via transseptal access to the Left Atrium (LA)
- After transseptal access, patients should be anticoagulated with intravenous heparin to maintain an ACT of > 300 sec
- Pre-ablation CT should be performed in all patients 
- In all patients pre and post pulmonary vein potentials should be recorded to confirm the isolation of pulmonary vein, with verification of entrance or exit block. 
-With any techniques, PV isolation should be performed as the gold standard. Additional line ablation or complex atrial fractionated electrogram (CAFÉ) ablation in RFCA group or posterior wall isolation in CB group can be done by the physician’s discretion, but strongly discouraged unless incessant LA tachycardia or recurrent IRAF is documented. 
- In CB plus group roof line ablation or posterior isolation should be performed. 
- Cavo-tricuspid isthmus ablation using irrigated radiofrequency catheter can be performed in all groups when CTI-dependent AFL was documented or induced. 
- If the patient is in atrial arrhythmia after completion of study procedure, sinus rhythm should be restored with DCCV by protocol
- inducibility test will be performed using isoproterenol (up to 10 mcg/min) with or without rapid atrial pacing (up to 180ms) to reveal the non-PV trigger as well as to assess the post-ablation AF inducibility. 19-22 The protocol for the inducibility testing may change depending upon the patient’s condition or attending physician’s decision,and should be recorded in the CRF. AF will be considered inducible if it persists for ≥1 minutes
- Ablation of non-PV trigger will be allowed if the repetitive triggers are noted during isoproterenol infusion.

상세내용 영문

	The method of ablation, use of contact-force sensing catheter or automatic tagging modules will be directed by the participating center’s policy or physician’s discretion. Following ablation strategies are recommended for all participants. Linear ablation or CFAE ablations are strongly discouraged by the protocol   
	When CARTO system (Biosense-Webster, USA) was used: AI guided ablation akin to the “CLOSE protocol” is recommended.23 Using Navistar Smart-touch surround-flow catheter; delivering 25-40 watts of energy; 40 seconds time limit; 10-30 gram of contact force; 40 seconds of time limit; targeting AI value of 550 in anterior wall and 400 in the posterior wall; interlesion distance ≤6mm; using automatic lesion annotation (Visitag™) – type 3 tagging, 3mm stability for 5 seconds, force >5g over 50% of time; target AI value could be reduced (450 in anterior wall and 350 in posterior wall) according to the participating center’s policy.24-26 
	When Ensite NavX system (Abott, USA) was used: Using TactiCath™ Quartz ablation catheter; delivering 25-35 watts of energy; 540 seconds time limit; 10-30 gram of contact force; using automatic lesion annotation (Automark Module), target lesion index value of 5-5.5 in the posterior wall and 5.5-6 in the anterior wall.

상세내용 영문

	The method of ablation, size of balloon, freezing time, and booster freezing will be made upon the participating center’s policy or physician’s discretion. Following ablation strategies are highly recommended for all participants. 27 Additional Linear ablation or CFAE ablations are strongly discouraged by the protocol
	Application of TTI + 2 minutes or 180 seconds single-freezing is recommended when time-to-isolation (TTI) <60 seconds. Additional 120 seconds of booster-freezing after TTI + 2 or 180 seconds initial freezing is recommended when TTI value >60 seconds, or PV potentials were not discernable in the Achieve multipolar catheter. If temperatures below <-40 ‘C cannot be achieved due to improper occlusion or TTI > 90 seconds, freezing should be discontinued and reposition of balloon is recommended. Segmental ablation is allowed when the proper occlusion of PV by balloon cannot be achieved. Continuous phrenic capture should be monitoring during procedure in the right PVs to avoid phrenic nerve injury. Stop ablation immediately if phrenic nerve damage is suspected. No further ablation would be performed when the phrenic nerve damage is suspected. Touch-up ablation using irrigated radiofrequency ablation catheter would be permitted with conventional mapping method.

상세내용 영문

	The method of ablation, size of balloon, freezing time, and booster freezing will be decided by the participating center’s policy or physician’s discretion. Ablation strategies described above are highly recommended for all participants. 27 
	Additional posterior wall isolation should be performed by single 120 to 180 second cryo application delivered at each site. 
	Utmost debulking of posterior wall should be attempted although complete posterior wall isolation may not be successful, as we considered that a large scare created by the CB application would provide sufficient anti-arrhythmic effects in terms of suppressing AF. The number and duration of cryo application should be recorded in the case report form.  
	Successful posterior wall isolation should be determined by one of the following methods. The method and achievement of posterior wall isolation should be recorded in the case report form.
	Entrance and Exit block of posterior wall with high-voltage pacing from achieve catheter or
	Bidirectional block of roof line by differential pacing or
	Reduction of the electrical activity (<0.1mV) in the left atrial posterior wall in the 3D-mapping system

영문

Persistent atrial fibrillation

영문

Freedom from documented atrial arrhythmia episodes lasting > 30 seconds without antiarrhythmics medications (after 3 months of blanking period)

영문

3 months after index procedure

영문

-	Atrial arrhythmia recurrence during blanking period (3 months) after one or two procedures with/without antiarrhythmic medications -	Atrial tachycardia or flutter recurrence during long-term follow-up ) after one or two procedures with/without antiarrhythmic medications -	Atrial fibrillation recurrence during long-term follow-up) after one or two procedures with/without antiarrhythmic medications -	Incidence of peri-procedural complications (including stroke, cardiac tamponade, esophageal injury, phrenic nerve damage, and death)  -	Rate of first-pass isolation or first-freeze isolation (%) -	Procedure duration (minutes) -	Ablation time (minutes) -	Fluoroscopy time (minutes) -	Procedure time (minutes, skin to skin) -	LA dwelling time  -	Ablation time (seconds) -	Quality of life changes at 12 months compared to baseline  -	Number of repeat procedures -	AF burden at 12 months after ablation assessed by 2-week patch monitoring -	LA pressure, mmHg (max/min/mean) after septal puncture and after procedure  -	Role of 2-week patch electrode in the detection of post-procedure atrial tachyarrhythmia in comparison to conventional Holter monitoring

영문

3 and 12 months after index procedure