**1. Introduction**

Atrial fibrillation (AF) is the most common sustained arrhythmia in the United States. Symptoms vary widely, and can include: palpitations, dizziness, chest discomfort, fatigue, shortness of breath, and stroke [1]. There are many factors that can increase one's risk of developing AF which include: age, increased body mass index (BMI), hypertension (HTN), diabetes mellitus (DM), congestive heart failure (CHF), obstructive sleep apnea (OSA), and some genetic predispositions as well. In addition to these risk factors, certain lifestyle characteristics can also play a role in the development or perpetuation of AF. These factors include smoking, alcohol, and psychosocial stress [2].

For patients with AF, the two principal goals of long-term therapy are to improve quality of life (e.g., symptom control) and to prevent associated morbidity and mortality. Rate and rhythm control strategies both can improve symptoms, but interestingly, neither has been conclusively shown to improve survival compared to the other. For those patients in whom a rhythm control strategy is chosen, catheter ablation

or antiarrhythmic drugs are the two principal therapeutic options. This chapter will review the efficacy and safety of these two options for rhythm control and provides rationale for choosing one versus the other [3].

The incidence and prevalence of AF has been increasing globally. Data from the Framingham Heart Study demonstrated that the prevalence of AF increased 3-fold over the past 50 years [4]. The prevalence of AF doubles with every decade of life and reaches close to 9% in the ninth decade. In 2019, AF was mentioned on over 180,000 death certificates and was the underlying cause of death in approximately 15% of those deaths. According to the CDC, it is estimated that more than 12.1 million individuals in the United States will have AF in 2030. The worldwide prevalence of AF was approximately 46.3 million individuals in 2016 [5]. In Europe, the prevalence of AF in 2010 was 9 million among people older than 55 years and is expected to reach around 14 million by 2060 [6].

Clinically, AF can be classified by the duration of episodes and responsiveness to therapies as follows:


AF is a complex process that results in rapid and disorganized atrial activation. Understanding the mechanisms of AF helps to understand the rationale behind the therapeutic interventions. The triggers for AF episodes most commonly are premature atrial contractions (PAC) which originate from within the pulmonary veins (PVs). Increased time in AF leads to structural changes throughout the atria such as scarring and fibrosis. These changes decrease the likelihood of spontaneous conversion to normal sinus rhythm (NSR) in patients with persistent or permanent AF [2, 7, 8].

The goal in circumferential pulmonary vein isolation (PVI) is to electrically separate the left atrium from the source of the PAC foci within the pulmonary veins. Circumferential pulmonary vein ablation has several putative mechanisms of action and is the mainstay for ablative treatments for AF. Other mechanisms by which circumferential ablation is believed to be effective are by concomitant ablation of the autonomic ganglia, which are found near the pulmonary vein ostia. Circumferential ablation is typically recommended for patients with PAF; however, it can also be beneficial for patients with persistent AF alone or in combination with additional ablation sites.

### **2. Catheter ablation vs. antiarrhythmic drugs**

For patients with either paroxysmal or persistent AF who desire sinus rhythm, catheter ablation or long-term antiarrhythmic drug therapy are the two available approaches. There are defined risks and benefits to the different approaches. This

section will review the studies that have directly compared them. It is important to note that this section is not intended to address management of patients who have failed rhythm control with two or more antiarrhythmic drugs or those who have already received catheter ablation. Antiarrhythmic drug therapy failure is defined as a trial of a drug that results in reduction in AF burden that is not satisfactory to the patient, or results in side effects that are intolerable to the patient, proarrhythmic, or result in organ toxicity [9, 10]. Prior to the 2020 ACC / AHA / HRS guidelines, catheter ablation (CA) was generally recommended as second line therapy after failure of AADs. However, mounting evidence suggested that CA is superior to AAD for the control of symptoms and maintenance of NSR. CA is now accepted as a first-line therapy for symptomatic patients after a comprehensive discussion of the benefits and risks of both approaches [3, 11].

Typically, evaluation of the various AF treatment strategies includes reference to the time free of AF in the year following treatment initiation. This is commonly referred to as the 1 year AF free survival. The 1 year data commonly excludes the 90-day blanking period following treatment to allow for post-ablation healing. An AF free survival of 100% would mean no patients had AF recurrences, and 0% 1 year AF free survival would mean all patients studied had recurrence within a year. Three early meta-analyses of studies comparing catheter ablation and antiarrhythmic drug therapy found that AF free survival was higher in the ablation treatment arm as compared to the AAD treatment arm [12, 13]. In the EARLY-AF trial, 303 patients were assigned to either AAD group (n = 149) or cryoablation group (n = 154). All the patients in both groups received an implantable cardiac monitoring device to assess AF recurrences and the follow-up period was 12 months. The first documented atrial tachyarrhythmia included for analysis had to occur between 91 and 365 days after CA or AAD initiation. The AF free survival was 89% of patients who underwent CA and 74% of the patients who were started on AAD (hazard ratio, 0.39; 95% CI, 0.22 to 0.68) [14]. Another study demonstrated similar results, which reported an 1-year AF free survival of 58% of patients undergoing CA and 32% of patients assigned to AAD therapy (hazard ratio, 0.48; 95% confidence interval [CI], 0.35 to 0.66; P < 0.001) [15]. In another trial that included 203 patients, 104 underwent CA and 99 received AAD therapy. In the ablation group, the procedure had initial success in 97% of the patients. The 1 year AF free survival was 74.6% (95% confidence interval, 65.0 to 82.0) in the ablation group and 45.0% (95% CI, 34.6 to 54.7) in the drug-therapy group (P < 0.001) [16, 17].

Important complications of AF ablations include cardiac tamponade (about 1%), pulmonary vein stenosis (<1%), phrenic nerve paralysis (~ 3%with cryoballoon), and rare instances of stroke and atrioesophageal fistula. Of the 303 patients in EARLY-AF, serious adverse events occurred in 5 patients in the CA group (3.2%) and in 6 patients (4%) of patients in the AAD group. Commonly prescribed drugs to maintain sinus rhythm are amiodarone, sotalol, dofetilide, dronedarone, flecainide, and propafenone. These medications range in efficacy from 40 to 60% 1 year AF free survival in meta-analyses. Important AAD medication side effects include proarrhythmia, bradyarrhythmia, organ toxicity, and death [17]. AAD selection is influenced by the patient's comorbid conditions such as CHF, CAD, structural heart disease, kidney function, and liver function. Guidelines exist to help in the selection of the appropriate agents with these comorbid conditions in mind to minimize potential drug toxicities and side effects. However, the guideline adherence when prescribing these medications is poor [18]. Importantly, all patients need to be informed of the possibility of recurrence of AF and adverse events with both catheter and medication-based rhythm control strategies.

Evaluating RF ablation versus AAD, the ThermoCool AF study randomly assigned 167 symptomatic patients with PAF who failed at least one AAD and who experienced at least three episodes of paroxysmal AF within the six months prior to randomization to either catheter ablation (with RF) or AAD therapy. Patients with significant left ventricular dysfunction, persistent AF, and advanced heart failure were excluded. Catheter ablation included PVI with confirmation of entrance block, and AAD therapy included flecainide (36 percent), propafenone (41 percent), dofetilide, sotalol, or quinidine at the investigator's discretion. After nine months, there were significantly fewer patients with documented symptomatic paroxysmal AF in the catheter ablation group (84 versus 34 percent AF free survival; hazard ratio 0.30, 95% CI 0.19–0.47). In addition, major treatment-related adverse events occurred more often with AAD therapy (9 versus 5 percent) at 30 days. Mean quality-of-life scores improved significantly with catheter ablation compared to AAD therapy [19].

A similar trial to ThermoCool AF was conducted for the cryoballoon catheter. The STOP AF trial is an important trial that specifically studied the use of AADs versus CA in patients with PAF. There were a total of 245 patients studied, all with either a diagnosis of PAF or persistent AF. All the patients included in the study had a history of previous AAD failure. In the AAD group, patients were randomly assigned to flecainide, propafenone, or sotalol. A "blanking period" was used in this study, which essentially allowed for medical optimization of any AAD or necessary re-ablation in the CA group. Treatment success was defined as the freedom from any detectable AF after the blanking period. The patients in both the experimental groups were followed for twelve months following intervention. Among those in the AAD group, 78% with PAF and 22% with persistent AF experienced failure of at least one AAD. On the other hand, 98.2% of patients in the CA group achieved acute isolation in three or more of the PVs, and 97.6% in all four PVs. A 1-year AF-free survival was found in 69.9% of CA patients, and 7.3% of patients in the AAD group. Among those patients who underwent CA, symptoms were significantly improved at the twelve-month mark as well [20].

The Catheter Ablation vs. Antiarrhythmic Drug Therapy in Atrial Fibrillation (CABANA) trial was a more recent large clinical trial looking at catheter ablation versus AAD in patients with AF. This study also evaluated patients with either paroxysmal (43%) or persistent AF (57%) and randomly assigned each patient to either AAD or CA therapy. Patients were excluded from the study if they had any prior catheter ablation procedure or failure of two or more antiarrhythmic drugs. It is important to note that in this study, of the patients who received AAD drug therapy, 27.5% crossed over to the ablation group. The primary endpoint of this study was death, disabling stroke, serious bleeding or cardiac arrest, which occurred in 8.0 and 9.2% in the AAD and CA groups, respectively during the 4 year follow up period. There was no significant difference in all-cause mortality (5.2% vs. 6.1%) among both respective groups. The trial showed that the combined end point of death or cardiovascular hospitalization occurred less often among those who underwent CA as it did for recurrence of AF. The quality of life scores for each group showed significant improvement. However, those in the CA group reported significantly greater improvement than the drug therapy group at twelve months with scores of 86.4 and 80.9 points, respectively, with a baseline reference value of 63 points [21].

To further assess the efficacy and safety of CA as compared to AADs as first line treatment for PAF, a meta-analysis was conducted of six studies that compared CA with AAD. Among studies in the meta-analysis, a total of 1200 patients were included. Catheter ablation was associated with lower rates of recurrent atrial

#### *Frozen Hearts: The Emerging Role of Cryoablation for Pulmonary Vein Isolation DOI: http://dx.doi.org/10.5772/intechopen.105885*

arrhythmias consistently. The risks of serious adverse events, including stroke, cardiac tamponade, and death were also evaluated. It was demonstrated that lower rates of symptomatic atrial arrhythmias, lower healthcare resource utilization, and lower rates of crossover to alternative treatment were all associated with first line CA strategy. However, this particular meta-analysis did have limitations which included a moderate degree of heterogeneity among the included studies most notably the RAAFT 2 trial [22].

The CASTLE AF trial demonstrated improved outcomes with upfront ablation among patients with chronic systolic congestive heart failure who are otherwise receiving appropriate treatment [21]. CASTLE AF used implantable cardioverter defibrillators equipped with AF monitoring capabilities to study AF recurrences in patients after randomization to initial catheter ablation or AAD therapy. Patients were excluded if they had a prior history of daily use of class I or class III antiarrhythmic drugs. The primary endpoint was considered to be death or hospitalization for worsening heart failure, and this was demonstrated in significantly fewer patients in the CA group in comparison to the AAD group. After a 60 month follow up period, 63.1% of the patients in the CA group and 21.7% of patients in the AAD group remained in sinus rhythm. In other words, the CA patients had a significantly lower recurrence of AF than those in the AAD group. In terms of mortality, fewer patients in the ablation group (28.5%) in comparison to the AAD group (44.6%) experienced the primary endpoint of death from any cause [10, 23].

In summary, CA is useful for symptomatic paroxysmal AF as a first line therapy when a rhythm control strategy is desired. Catheter ablation for AF is safe and effective with similar or improved outcomes as compared to AADs for long term AF management with fewer long-term complications. Upfront catheter ablation as noted in the CASTLE-AF trial is associated with reductions in all-cause mortality in patients with CHF. A discussion with patients regarding these risks and benefits should guide decisions on which strategy to utilize in the maintenance of normal sinus rhythm (NSR).

## **3. Cryoablation vs. radiofrequency**

Catheter ablation is now a well-established interventional approach for treating symptomatic, drug refractory PAF with class I level A guidelines recommendation. A 2017 randomized comparison between cryoablation and RFA showed similar success rates, as did a meta-analysis of observational studies. Historically, catheter ablation using either cryoablation or radiofrequency ablation demonstrated 60–80% 1 year AF free survival.

Cryoablation for arrhythmias has been used for cardiac surgery for decades. However, transvenous catheter cryoablation for arrhythmias have been used only since the 2000s. The main purpose of cryoballoon ablation (CBA) is to isolate pulmonary veins (PVs) with single energy application for encircling lesions at the antral level of the PVs. Conventional radiofrequency catheter ablation (RF) was characterized by point-by-point ablation to create a line which requires multiple energy applications to accomplish PVI [24].

The procedure of cryoablation is performed in the cardiac catheterization / electrophysiology laboratory. Access is typically obtained through the right femoral vein. Additional access is often required from the left femoral vein and/or the axillary or internal jugular vein depending on the operator's preference. The ablation technique

for cryoballoon ablation is similar to that of radiofrequency ablation in that a septal puncture is used to access the left atrium with the goal of PVI. In the case of cryoablation, only a single transseptal puncture is required though at a lower anterior septal location. This location is recommended to allow more space for the cryoballoon to move and provide better support to the PVs, especially the right inferior PV [10].

With the assistance of fluoroscopy, and 3D electroanatomical mapping technologies including intracardiac echocardiography; transseptal puncture is performed to gain access to the left atrium. The ablation can be made in any sequence, but it is commonly started with the left superior pulmonary vein then left inferior pulmonary vein followed by the right inferior pulmonary vein and finally the right superior pulmonary vein [1]. Esophageal temperature monitoring is frequently performed to avoid potentially dangerous cooling of the esophagus during adjacent LA cryoablation. Similarly, the right phrenic nerve is paced during right-sided pulmonary vein applications to avoid phrenic nerve damage. After ablation is completed, a mapping catheter is placed into each pulmonary vein to check for proper electrical isolation. A vein is considered acutely isolated if it demonstrates entrance and exit electrical block [25].

Radiofrequency is completed using a current which is applied in a point-by-point method. The resistive current allows for the tissue to be heated, and this results in cellular necrosis. Alternatively, the use of cryothermal energy, which is applied with a balloon, differs from the former as it allows for cellular necrosis via freezing [24]. Cryoballoon technology is increasingly used for treating AF. Although commonly there are 2 right-sided and 2 left-sided pulmonary veins, there are frequently noted anatomical variants. Cryoballoon ablation for PAF was associated with similar clinical outcomes as radiofrequency independently of the anatomical pulmonary vein distribution pattern. The presence of a left common ostium or right middle vein was found to have similar clinical outcomes after cryoablation when compared with a control group treated by standard radiofrequency ablation. Pulmonary vein anatomical variants should not influence the choice of cryoballoon ablation [26].

There are many studies that compare the efficacy of cryoballoon ablation to radiofrequency, and a few of those trials have been outlined below. However, it is important to note that many of these studies involve relatively small sample sizes which are accompanied by a number of confounding variables. Systematic literature reviews and meta-analysis evaluating efficacy of cryoablation versus radiofrequency ablation for treating paroxysmal AF are helpful to make comparisons in this light [10, 26]. In a meta-analysis by Yi-He Chen et al., of 273 scholarly articles containing comparison between radiofrequency ablation and cryoablation of PAF. There were a total of 7195 participants studied, approximately one third (2863) underwent cryoablation and two thirds (4332) underwent RF ablation. The mean age of the patients was 59.9 years old, with a history of PAF ranging from 2.1 to 5.2 years. The study types included were retrospective cohort and prospective cohort with one study being ambi-directional. Cryoablation of the pulmonary vein was performed with a second generation cryoballoon within the majority of the studies. The mean follow-up duration ranged from 12 to 18 months. There is no evidence of significant differences for patient baseline demographic characteristics between the CA and RF ablation groups [26]. The overall freedom from AF/atrial tachycardia relapse was 65.6% with CA and 60.1% with RF ablation in follow-up of 12 months. The pooled estimate of relative risk ratio indicated that PVI was achieved by CA and RF ablation, which lead to comparable long-term AF/atrial tachycardia free survival during follow-up. Relative risk was 1.05 with a 95% confidence interval of 0.98–1.13, P = 0.159. There were no statistically significant

#### *Frozen Hearts: The Emerging Role of Cryoablation for Pulmonary Vein Isolation DOI: http://dx.doi.org/10.5772/intechopen.105885*

interactions between the pooled RR and prespecified covariants. Data on procedure related adverse events were available for meta-analysis in 15 studies. Events occurred in 223 of 2759 patients (8.08%) with cryoablation and 333 of 4130 patients (8.06%) with RF ablation. No significant difference was found between these 2 approaches for ablation procedure-related adverse events [26].

The *FIRE AND ICE* trial, the largest prospective multicenter comparison between the two techniques, demonstrated that the cryoballoon is noninferior to radiofrequency ablation (RFA) in efficacy. The primary efficacy endpoint was defined as the first documented clinical failure (recurrence of AF, episodes of atrial flutter, start of antiarrhythmic agent, or repeat ablation). The study also demonstrated no significant difference with regards to overall safety. There were no reports of deaths, esophageal fistulas, or pulmonary vein stenosis. With regards to concerns about phrenic nerve injury the study showed only 1 in 300 patients developed permanent phrenic nerve injury at 12 months.

There was no significant difference in fluoroscopy time between the 2 approaches but overall procedure time in CBA was significantly less. This is due to the fact that CBA is a 1-shot catheter rather than the point-by-point approach in RF ablation to achieve pulmonary vein isolation. The point-by-point RF mapping has a more complex learning curve as it requires great skill and is more technical than CBA. This is what is making CBA one of the most widely used catheter techniques.

RF ablation results in irreversible tissue damage via heating. In CA, the freezing process involves ice crystal formation. This allows for an osmotic gradient to develop, which subsequently leads to acute cell death. This mechanism of cell death involves cellular swelling and disruption of the membrane integrity by means of further osmotic insult. The histopathological features of CA may be responsible for relatively demarcated lesions with minimal tissue architectural disruption. This has been found to contribute to a lower risk of thrombus formation and perforation. In addition, cryoballoon CA has also demonstrated catheter adhesion to pulmonary vein (through freezing) and thus the prevention of dislodgement [27, 28].

The long-term freedom from AF at 12-month follow-up and overall postoperative complication rates is also important to evaluate. One meta-analysis reviewed 247 articles, with a total of 8 studies encompassing 1548 patients who underwent either cryoballoon or radiofrequency ablation. This is representative of data from Europe between 2012 and 2015. Overall, it was found there is no significant difference between the freedom from AF after 12 months between both groups cryoballoon and radiofrequency ablation. Secondary outcomes during the ablation at the fluoroscopy time the ablation time failed to reach significance as well. Cryoablation had a significantly greater odds of postop phrenic nerve injury after 12 months [29].

A novel way of comparing the effectiveness of cryoballoon ablation and radiofrequency ablation was demonstrated by Trippoli et al. with a pooling method referred to as the Shiny method. The Shiny method is based on an artificial intelligence that reconstructs individual patient data. Using the Shiny method is unique because it accounts for follow-up length. This method was used for reevaluation of a metaanalysis. The advantage to using this method in re-analysis is because researchers are able to evaluate the probability of the end-point in the long term. The primary endpoint was time to recurrence of AF in patients who were enrolled in randomized studies comparing CA to AAD, RF to AAD, and CA to RF. Overall, CA showed a statistically significant higher effectiveness than AAD therapy. In the comparison of AAD to RF, no statistically significant difference was observed. This suggests that the results generated by the Shiny method from previously published meta-analysis were able to account for the effects of randomizations performed in the trials, along with accounting for length of follow up in the individual trials [30].

Atrial esophageal fistula is a well described complication of RF ablation where an abnormal potentially life-threatening connection forms between the esophagus and right atrium by a mis-match repair mechanism. It is hypothesized that this occurs due to inflammation caused by energy delivery to the posterior wall of the left atrium adjacent to the esophagus. Although initially believed to be a unique complication related to RF ablation, cryoablation has also been associated with this potentially fatal complication though far less frequently. A study by Ripley et al. dives further into the adverse effect of esophageal lesions after catheter ablation with cryoballoon and RF ablation and the implication for atrial esophageal fistula formation. The effects of direct application of RF and cryoablation on the cervical esophagus were evaluated in 16 calves. Cryoablation was performed with a 6.5 mm catheter probe using a single 5-minute freeze at less than −80°C. RF ablation was delivered with an 8 mm catheter electrode at 50 W and 50°C for 45 to 60 seconds. Histopathological assessments were performed at 1, 4, 7, and 14 days after the completion of both ablation procedures. This article evaluated the direct application of cryoablation and RF ablation in the left atrium and its effects on the esophagus. Although, on day 14 lesions in both groups on the esophagus were comparable in size, there was histological evidence of partial to full wall esophageal lesion ulceration associated with 0 of 44 cryoablation lesions and in 9 of the 41 lesions with RF ablation (P equals 0.0025). In other words, Cryoablation was associated with a significantly lower risk of esophageal ulceration [30].
