Ultralow temperature cryoablation using near‐critical nitrogen for cavotricuspid isthmus‐ablation, first‐in‐human results

Abstract Introduction Cryoablation has evolved as a safe alternative to radiofrequency ablation in the treatment of several supraventricular arrhythmias and has potential advantages, yet is limited by the properties of the cryogen used. We investigated a novel ultralow temperature cryoablation (ULTC) system using nitrogen near its liquid‐vapor critical point as a freezing source, achieving temperatures as low as ‐196 degrees Celsius in a long linear catheter with a continuous energy release. Initial safety, procedural and efficacy outcomes of ULTC are described in patients undergoing cavotricuspid isthmus (CTI) ablation. Methods and Results The Cryocure studies (NCT02355106, NCT02839304) are prospective, single‐arm, multi‐center, first‐in‐human clinical studies in 17 patients with atrial flutter (AFL) and 13 patients with atrial fibrillation (AF). A total of 30 patients, mean age 65 ± 8 years old and 67% male, were enrolled and underwent ablation of the CTI. Acute success, defined as the confirmation of stable bidirectional conduction block across the CTI, was achieved in all 30 patients. After 12 months of follow‐up, 14 out of 17 AFL patients remained free from any AFL. One (3.3%) procedure‐related but not device‐related serious adverse event was reported, involving transient inferolateral ST‐elevation associated with temporary AV conduction block. Conclusion In this first‐in‐human clinical study the safety and performance results demonstrate the capabilities of ultralow temperature near‐critical nitrogen as an effective energy source for CTI ablation. Ongoing, larger, studies should confirm our findings and evaluate the capabilities to create linear and focal transmural lesions in other arrhythmias.

K E Y W O R D S cavotricuspid isthmus, cryoablation, first-in-human, near-critical nitrogen, ultralow temperature

| INTRODUCTION
Ablation treatment has acquired a prominent role in the treatment of supraventricular arrhythmias, leading to an increasing demand for operating rooms and operator time. New technologies aim to improve the efficacy, speed and durability of ablation treatment. Cryoablation has evolved as a safe alternative to radiofrequency (RF) ablation in the ablation of supraventricular arrhythmias. [1][2][3][4][5][6] Potential advantages of cryothermal energy are catheter stability due to adherence to myocardial tissue, the ability of reversible cryomapping mitigating the risk of permanent damage to critical structures like the atrioventricular (AV) node, a low risk of thrombus formation and systemic embolization, and a low probability of myocardial perforation due to the preservation of tissue architecture. 1,2,5,[7][8][9][10] Yet, efficacy of cryoablation using gaseous cryogens may be hampered by physiological reversibility of cellular injury when ablation times are too short or freezing temperatures not low enough, allowing thicker areas of myocardium to recover from freezing injury and recurrence of arrhythmias to occur. 11,12 The efficiency and speed of cryoablation is first and foremost determined by cryogen that is used in the ablation catheter. Classic cryoablation systems have used gaseous cryogens (predominantly nitrous oxide gas [N 2 O]), which have a much lower thermal capacity due to their small density when compared to liquid cryogens. This limits the catheters' overall cooling power, cooling speed, minimum temperature and effective cooling surface, while resulting in a massive gas consumption, mandating multiple applications (freeze-thawcycles) of several minutes. [12][13][14][15] Although liquid cryogens possess much higher thermal conduction and greater heat capacity than N 2 O, they are difficult to handle in endovascular catheters and considered unreliable and unsafe. Nitrogen near its liquid-vapor critical point (near-critical nitrogen) provides a unique solution that can be used in cardiac applications. Owing to its very low viscosity, it can be flowed down tiny channels while providing a freezing capacity that can overcome endovascular heat sinks. This new concept of near-critical cooling makes it possible to maintain an uninterrupted flow of a cryogen close to its critical state along the full catheter length. It also solves issues related to slow "start-stop" times present in liquid cryogen flow systems, limited to larger probe sizes. 12 Recently, Adagio Medical has developed a novel cryoablation system using near-critical nitrogen as a freezing source, achieving temperatures as low as −196°C in a 9F linear catheter with continuous energy release.
This could overcome many of the efficiency and speed limitations with prior cryoablation platforms. Preclinical data demonstrated that ultralow temperature cryoablation (ULTC) is highly effective and capable of creating durable, transmural and contiguous atrial and ventricular lesions in an in vivo model in large animals. 16 In this first-in-human study, we describe the initial safety and efficacy outcomes using the Adagio ULTC system to create durable bidirectional cavotricuspid isthmus (CTI) conduction block.   provides the conduit for the Cryoablation catheter to be placed near the targeted tissue to be ablated. The size and geometry of the catheter freezing zone (distal tip) can be customized to suit the desired target for ablation using a stylet. The catheter can be used in a linear convex, concave or circular shape, as well as focal. For CTI ablation, using a linear convex or concave approach, it is designed to easily contact and cover the CTI tissue, allowing for a single freeze once appropriate contact is made between the distal tip of the catheter and the CTI. The convex approach may overcome pouches along the CTI. The correct catheter position within the CTI is verified by using both fluoroscopy and the catheter electrodes, which enable verification of tissue contact and correct location of the cryoablation element within the right atrium. This makes its positioning easier, shortens the procedure time, and eliminates the need for an additional diagnostic catheter. The use of an electro anatomical mapping system is possible but not mandatory.

| Electrophysiology study and ablation
Subjects were treated under conscious sedation or general anesthesia (GA) and prepared for ablation according to local standard. The procedures were performed under continued oral anticoagulation with vitamin K-antagonists (target international normalized ratio between 2.0 and 3.0) or uninterrupted non-vitamin K oral anticoagulants. All patients were then given an intravenous heparin bolus based on their weight.
Once the cryoablation catheter was placed at the target ablation sites, freezes of one minute (limited to two minutes) in duration were performed along the CTI. Applications were continued until there was clear evidence of bidirectional conduction block (BCB). Repeat documentation of BCB was performed at a minimum of 30 min following the last ablation.
BCB was confirmed using standard pacing methods and considered stable BCB if no conduction recovered. If conduction recovered, additional ablations were allowed, and the process for BCB verification at 30 min postablation was reinitiated. The use of isoproterenol for additional assessment of isthmus conduction was allowed at the investigators' discretion. At the completion of all ablation and mapping procedures, catheters and sheaths were removed, and hemostasis was obtained following the institutions standard of care. There were no pre-specified requirements for length of stay or resumption of medications including, anticoagulation or antiarrhythmic drug therapy.

| Post-ablation management and follow-up
All patients were monitored in hospital for 24 h. In the follow-up phase of the study, two clinic visits were scheduled, followed by standard of care follow-up until 12 months after the ablation procedure. During the clinic visits, a medical history, physical examination and 12-lead ECGs were examined for an evaluation of patient arrhythmia status and any evidence of adverse events. Holter monitoring or event monitoring was performed when symptoms occurred and was left at the discretion of the treating physician. Additional follow-up was collected up to 12 months after the procedure according to the hospitals' standard of care. All ECGs, continuous ECG monitoring and repeat electrophysiology studies (EPS) were reviewed for recurrent arrhythmias.

| Outcome measures
The primary objective of the study was to provide data on the safety of ULTC using the Adagio medical device for CTI ablation. All safety KLAVER ET AL.

| Data collection
Data collected at all visits were entered through a web-based electronic data capture system. The data were monitored following ISO 14155, Good Clinical Practice and in compliance with the Clinical Monitoring Plan. Maintenance of the study database was performed by the sponsor. As needed, data clarification requests were issued to sites and resolved to completion. The data underlying this article were provided by the sponsor. Data will be shared on request to the corresponding author with permission of the sponsor.

| Statistical analysis
Descriptive statistics for all variables were applied. For continuous variables, mean and standard deviation or median and interquartile range, minimum and maximum were reported. For ordinal and categorical variables, counts and percentages were applied.

| RESULTS
In a total of 30 patients, CTI ablation was performed; 17 from the CC1 cohort and 13 from the CC2 cohort (mean age was 65 ± 8 years old and 67% male). All patient characteristics are shown in Table 1.
Procedural data are summarized in Table 2. CC1 patients were the first to be treated with the cryoablation system, while the CC2 patients were all part of a subsequent study.

| Safety results
Safety data was available in all patients. There was one serious adverse event reported among 30 patients ( Table 3). The event consisted of transient ST-elevation in the inferolateral limb leads of the 12-lead ECG associated with a temporary AV conduction block, during a procedure in which GA was used. No medications were administered, and the ECG changes resolved spontaneously within a minute, including normal AV conduction. At the completion of the procedure, the patient was awake and free of symptoms. The patient was discharged the following morning as per standard hospital protocol postablation. The discharge and follow-up ECGs showed sinus rhythm with normal AV-conduction. The DSMB classified the event as serious, severe in intensity, and related to the procedure but not related to the device. The cause of the event was attributed to vasospasm of the right coronary artery due to a lateral placement of the cryoablation catheter.

| DISCUSSION
This is the first-in-human clinical trial evaluating the use of near critical nitrogen as a cryogen for catheter ablation of the CTI in 30 patients. This proof-of-concept study demonstrates that the Adagio cryoablation system is able to safely perform cryoablation of the CTI with encouraging acute and long-term success rates, while showing favorable procedure characteristics and minimal safety concerns.

| Acute success and procedural outcomes
We demonstrated acute efficacy in 30 out of 30 (100%) of patients, without the use of electro-anatomic navigation, while procedure and fluoroscopy times were reduced compared with those reported in literature. 14,17,18 A median of 3 + 1 bonus freeze was needed to achieve BCB and 40% of the patients showed BCB after the first freeze. In previous studies, acute success, defined as bidirectional conduction block, is reported in 85-97% of procedures and in agreement with our findings. 2,[18][19][20][21] In general, reported procedure times for cryoablation tend to be longer than procedures using radiofrequency ablation (120-246 min and 99-198 min, respectively). 22 Available cryoablation systems use a focal "point by point" energy delivery, requiring several freeze-thaw cycles of many minutes. 13,14 Ablation using RF requires shorter applications and has no additional thaw time due to the lack of catheter adhesion.
Using RF ablation, lines are created using a "drag and burn" method  The present study shows the ability to perform successful ablation of the CTI, but ongoing studies are directed to substantiate these findings and evaluate the capabilities to create linear and focal transmural lesions of the ablation system in other arrhythmias.
Currently, the iCLAS trial (NCT04061603) is a global, single-arm, clinical study designed to collect acute and long-term safety and efficacy data of the 4th generation Adagio AF Cryoablation System in a larger population. 200 patients with persistent AF will be enrolled and will receive PVI and linear lesions (posterior wall and CTI) with the improved version of the ULTC system.

| Study limitations
The main limitation of this first-in-human study is the exploratory nature, with a single-arm, uncontrolled design with a small sample size. Furthermore, the study population consisted of patients suffering from AFL (CC1) and/or AF (CC2). Recurrence of AFL is therefore not a valid endpoint for CC2 patients. Acute success (stable BCB) was seen in all patients, but the protocol did not include systematic repeat EPS after 2-3 months to reassess durable BCB.
Albeit multiple study visits were scheduled to investigate possible safety outcomes and symptoms, only limited scheduled repeat monitoring was performed with ECG or Holter, and additional monitoring was only performed in symptomatic patients. This may have overestimated the overall success rate. No serious adverse events leaving sequelae were seen, but larger studies are needed.
Finally, results may be influenced by the learning curve of both centers and ongoing trials are needed to confirm safety and longterm efficacy.

| CONCLUSION
In this first-in-human, thirty-patient clinical study, the safety and performance results demonstrate the capabilities of ultralow temperature near-critical nitrogen as an energy source for ablation of the CTI. One transient procedure-related adverse event (coronary artery spasm) was reported. Acute success was achieved in all subjects, while 82.4% remained free of AFL recurrence at 12-month follow-up. The ultralow temperatures achieved, the lower number and shorter duration of freezes compared to other cryoablation technologies suggest a high potential for this novel energy source.
Future studies will evaluate the capabilities of the system in larger sample sizes and other arrhythmias.