Atrial fibrillation (AF), the most prevalent cardiac arrhythmia, affects approximately 37.6 million individuals worldwide [1]. Without preventive treatment, AF recurrence is likely to occur in 90% of patients [2]. Current guidelines recommend antiarrhythmic drugs (AADs) as the first-line treatment for maintaining sinus rhythm in symptomatic AF patients [3, 4]. However, the effectiveness of AAD therapy is somewhat limited, and a significant proportion of patients discontinue treatment due to severe side effects [5, 6]. In cases of AAD ineffectiveness or intolerance, catheter ablation is recommended and has been shown to be superior to additional AAD therapy [7, 8, 9].

Since 2005, several randomized clinical trials (RCTs) have compared radiofrequency ablation with AAD therapy in patients without prior AF ablation or AAD usage [10, 11, 12]. These trials have shown a modest reduction in AF recurrence but an increased occurrence of serious adverse events with ablation compared to AAD therapy [13]. Cryoballoon pulmonary vein isolation (PVI), first introduced in 2003, has emerged as another recognized method for ablating AF [14, 15]. Three similar RCTs have reported on the comparison of cryoablation and AAD therapy as first-line treatments for symptomatic AF [16, 17, 18]. Several meta-analyses of these studies have demonstrated improved outcomes in terms of AF recurrence and hospitalizations, with no significant difference in major adverse events [19, 20]. However, few reviews have focused on the quality of life (QoL) and safety outcomes associated with cryoablation as a first-line treatment. Therefore, the aim of this systematic review and meta-analysis is to further evaluate the impact of cryoablation as a first-line therapy compared to drug therapy on the QoL and safety of patients with symptomatic AF.

A total of 4,197 articles were identified in the literature search, of which 7 articles (4 trials) [16, 17, 18, 23, 24, 25, 26] met the inclusion criteria and were included in the analysis (Fig. 1).

Fig. 1.

Selection process of included studies. RFA, radiofrequency ablation; CA, cryoablation; RCT, randomized controlled trial.

3.2 Primary Outcome

The improvement in QoL, assessed using AFEQT and EQ-5D scores, was reported in the EARLY AF, CRYO-FIRST, and STOP AF trials. Three studies with a total of 724 participants reported AFEQT scores as a follow-up outcome. Cryoablation was associated with a significant increase in AFEQT scores compared to AAD therapy (3 trials; MD: 7.46, 95% CI: 2.50 to 12.42; p = 0.003; I${}^2$ = 79%) (Fig. 2). Two studies with 506 participants reported EQ-5D and EQ-VAS scores as follow-up outcomes. Cryoablation demonstrated a significant improvement in EQ-VAS scores compared to AAD therapy (2 trials; MD: 1.49, 95% CI: 1.13 to 1.86; p 0.001; I${}^2$ = 0%) (Fig. 2) and no significant difference in EQ-5D scores (2 trials; MD: 0.03, 95% CI: –0.01 to 0.07; p = 0.07; I${}^2$ = 79%) (Fig. 2). The primary safety outcome, serious adverse events, was reported in all 4 trials included in the analysis. The rate of serious adverse events was significantly lower with cryoablation compared to AAD therapy (4 trials; 11.8% vs. 16.3%; RR: 0.73; 95% CI: 0.54–1.00; p = 0.05; I${}^2$ = 0%) (Fig. 3).

Fig. 2.

Forest plot illustrating QoL among AF patients randomized to cryoablation versus AAD therapy. (A) Forest plot illustrating AFEQT score among AF patients randomized to cryoablation versus AAD therapy. (B) Forest plot illustrating EQ-VAS among AF patients randomized to cryoablation versus AAD therapy. (C) Forest plot illustrating EQ-5D among AF patients randomized to cryoablation versus AAD therapy. QoL, quality of life; AFEQT, Atrial Fibrillation Effect on Quality-of-Life; EQ-VAS, European Quality of Life–visual analog scale questionnaire; EQ-5D, European Quality of Life–5 Dimensions; AF, atrial fibrillation; AAD, antiarrhythmic drug; SD, standard deviation.

Fig. 3.

Forest plot illustrating the safety outcomes among AF patients randomized to cryoablation versus AAD therapy. (A) Forest plot illustrating the rate of serious adverse events among AF patients randomized to cryoablation versus AAD therapy. (B) Forest plot illustrating the rate of overall adverse events among AF patients randomized to cryoablation versus AAD therapy. (C) Forest plot illustrating the rate of MACEs among AF patients randomized to cryoablation versus AAD therapy. MCAE, major adverse cardiovascular events; AF, atrial fibrillation; AAD, antiarrhythmic drug.

The principal findings of our meta-analysis provide valuable insights into the use of cryoablation as a first-line therapy for patients with symptomatic AF. We observed significant improvements in the AFEQT score with cryoablation compared to AAD therapy. However, there were no significant differences in the change in EQ-5D index score between the two treatment groups. Cryoablation also demonstrated a significant reduction in the risk of serious and overall adverse events, hospitalizations, and additional ablation compared to AAD therapy. However, there were no significant differences in major adverse cardiovascular events and emergency department visits. Importantly, we observed a lower rate of crossover to alternate therapy and additional ablation in the cryoablation group, indicating a potentially more effective and durable treatment approach.

Cryoablation has emerged as a promising approach for the treatment of AF since its introduction in 2003 [14]. This technique, characterized by a single-shot PVI, offers advantages in terms of ease of use for operators compared to the traditional “point-by-point” ablation method [27]. Numerous studies have confirmed the effectiveness of cryoablation in the treatment of AF [28]. A recent meta-analysis, which included 7195 patients from 16 studies, found similar rates of arrhythmia-free survival and adverse events between cryoablation and radiofrequency ablation, another commonly used ablation method. This suggests that cryoablation is a viable alternative with comparable outcomes to radiofrequency ablation [29]. In our analysis, all 4 trials included in the meta-analysis used second-generation cryoballoon catheters for cryoablation. These second-generation devices have demonstrated superior efficacy and a similar safety profile compared to the first-generation cryoballoon devices. This advancement in technology further supports the effectiveness and safety of cryoablation as a treatment option for AF. Overall, the evidence from our analysis and previous studies supports the validity and effectiveness of cryoablation in the treatment of AF. The use of second-generation cryoballoon (CB) catheters has further improved outcomes, making cryoablation a valuable therapeutic approach in managing cardiac arrhythmia [30].

Numerous studies have focused on comparing ablation with anti-arrhythmic drugs in patients who did not respond to drug therapy. However, recent trials have examined the use of ablation as the initial treatment for AF and compared it to drug therapy [10, 11, 12, 16, 17, 18]. In particular, one observational study demonstrated that cryoballoon-based PVI as the first-line treatment in treatment-naive patients with paroxysmal or persistent AF resulted in favorable outcomes with a 79.2% arrhythmia-free survival rate after 2 years of follow-up [31]. These findings suggest the potential of cryoablation as an initial therapy for AF in patients who have not previously received drug treatment. Previous meta-analyses comparing radiofrequency ablation with drug therapy as the initial treatment for AF showed a modest reduction in AF recurrence but no significant difference in symptomatic AF recurrence, cardiovascular outcomes, or repeated procedures [13]. Furthermore, more serious adverse events were found in the ablation arm. Recently, another meta-analysis showed a higher risk of hospitalization with ablation than with drug therapy in these three trials [32]. However, these studies reported a higher incidence of serious adverse events in the ablation group. A more recent meta-analysis, which included previous trials and three additional RCTs comparing cryoablation and drugs as the initial treatment for AF, reported improved outcomes in terms of AF recurrence and hospitalizations, with no significant difference in major adverse events [19]. It is worth noting that some information was not available for analysis due to data extraction from abstracts, and other analyses comparing cryoablation and drug therapy for initial treatment showed similar results regarding atrial arrhythmia recurrence and adverse events [20, 33].

In recent years, there has been an increasing focus on evaluating changes in symptoms and QoL with initial “first-line” therapy for paroxysmal AF [25, 26, 34]. The primary goal of AF treatment is to improve QoL and alleviate symptoms [4]. However, the clinical endpoints commonly used in cryoablation trials may not always align with the patient’s subjective perception of their overall well-being [35, 36]. Therefore, assessing QoL is crucial for a comprehensive evaluation of different treatment approaches, as it takes into account the participant’s subjective feelings about their health and considers the potential adverse effects of treatment strategies.

In our analysis, three trials evaluated QoL using various questionnaires such as the AFEQT questionnaire, the SF-36 questionnaire, and the EQ-5D and EQ-VAS questionnaires [16, 25, 26]. The AFEQT questionnaire specifically focuses on the QoL impacts of AF and is a sensitive and reliable measure for assessing disease-specific QoL [37]. We found that the AFEQT summary score significantly improved from baseline to the endpoint of follow-up in both the cryoablation and AAD groups, with a greater improvement observed in the cryoablation group. However, the results regarding general QoL tools were inconsistent. The EQ-5D and EQ-VAS questionnaires were applied in the EARLY AF and STOP AF trials, while the SF-36 questionnaire was used in the CRYO-FIRST trial. The STOP AF trial did not show significant between-group differences in the improvement of general QoL measures, which contrasts with the findings in EARLY AF and CRYO-FIRST. Despite the significant differences observed in EQ-VAS score in our analysis, it’s important to acknowledge that the results may carry limited significance, given that only two trials were included, and the analysis heavily favored one trial with a weight of 99.2%. These discrepancies may be attributed to the fact that general QoL tools do not specifically focus on the impacts of AF, potentially resulting in survey responses influenced by symptoms unrelated to the study intervention.

To assess the effect of initial rhythm control strategies on the progression of AF to a persistent form, two trials completed a 36-month follow-up [23, 24]. At 3-yearss, a significantly lower percentage of patients in the cryoablation group compared to the drug therapy group experienced progression from paroxysmal to persistent AF. Previous studies have reported that progression from paroxysmal to persistent AF occurs in 8–15% of patients at 1 year and in 22–36% of patients at 10 years after the initial onset of paroxysmal AF [23, 38, 39]. Several studies have shown that radiofrequency ablation is associated with lower rates of AF progression, and our analysis suggests that cryoablation may play a significant role in preventing the progression of AF to a persistent form [40, 41].

Safety outcomes, primarily assessed through adverse events, are a crucial consideration in the initial ablation treatment of AF. As an invasive procedure, ablation carries the potential for complications. Previous meta-analyses reported a higher incidence of serious adverse events associated with catheter ablation, although the difference was not statistically significant [13, 19]. However, our analysis suggested that cryoablation significantly reduced the rate of serious adverse events (11.8% vs. 16.3%) and overall adverse events (18% vs. 26.6%). Regarding major adverse cardiovascular events, the rates were 1.2% vs. 2.8%, which did not reach statistical significance. Importantly, there were no cases of death, atrio-esophageal fistula, stroke, major bleeding, or symptomatic pulmonary vein stenosis reported at the 12-month mark in the cryoablation group. After 12 months of follow-up, two deaths were reported in the EARLY AF trial, one of which was related to complications from acute pancreatitis in the ablation group, and the other was due to respiratory complications of amyotrophic lateral sclerosis in the drug therapy group [23]. The most common periprocedural complication observed was phrenic nerve injury, with six cases reported across the four trials, which is consistent with previous reports [31, 42]. Four cases (including one crossover case in CRYO-FIRST) of phrenic nerve injury were reversible during the follow-up period. While current guidelines recommend drug therapy as the first-line treatment for AF, it is important to note that drug therapy carries potential extracardiac and proarrhythmic side effects [43, 44]. In our analysis, 32 patients in the AAD arm discontinued AADs due to adverse effects, including withdrawal and crossover. It is worth mentioning that drug-related adverse events and procedure-related adverse events differ significantly. Additionally, the definition of major adverse events was not always consistent across the study designs, and many adverse events were uncommon or required long-term observation within the studies [45]. Thus, our analysis focused on serious adverse events, overall adverse events, and major adverse cardiovascular events. Nonetheless, a larger sample size and longer follow-up period would be necessary to thoroughly investigate the adverse event profile.

Crossover occurred in 5.3% of patients, with only three cases transitioning from cryoablation to AAD therapy. This crossover rate was lower than previously reported, primarily due to the restriction of crossover between groups in the EARLY AF trial [16]. Additionally, the rate of hospitalizations and the need for additional ablation after randomization were significantly lower in the cryoablation group compared to the drug therapy group. These findings provide further support for cryoablation as a superior first-line therapy option over pharmacological treatments in terms of safety. However, patient selection and operator experience should be taken into consideration when making treatment decisions.

Several limitations need to be acknowledged in the present analysis. Firstly, despite all the trials included in this study being randomized controlled trials, it is important to note that neither the patients nor the physicians were blinded. The absence of blinding may have influenced the observed benefits of ablation and introduced potential bias into the results. Secondly, despite significant improvements found in AFEQT scores with cryoablation compared to AAD therapy, the heterogeneity may influence the outcome. Thirdly, the trials included in this meta-analysis were limited and the patient population in this analysis comprised younger individuals with structurally and functionally normal hearts, which could restrict the generalizability of the findings to other populations of AF patients. The outcomes and treatment effects observed in this specific patient group may not necessarily apply to older individuals or those with underlying structural heart diseases. Fourthly, continuous monitoring was only implemented in the EARLY AF trial, whereas intermittent monitoring was employed in the other studies. This disparity in monitoring methods could have led to an overestimation of the outcomes in both treatment groups. Lastly, the drug therapy group allowed the utilization of class I and III ADDs, introducing variability in drug choice and dosing. The diverse utilization of various drugs and treatment regimens among patients might have influenced the outcomes, and inadequate treatment of some patients may have contributed to an increased recurrence of atrial arrhythmias.

In conclusion, our meta-analysis demonstrates that cryoablation, when employed as a primary treatment modality for patients afflicted with symptomatic AF, yields substantial enhancements in AF-specific QoL and notable reductions in serious adverse events, the incidence of persistent AF, hospitalizations, and the need for additional ablation when compared to ADDs. Notably, no statistically significant disparities were discerned in general QoL, major adverse cardiovascular events or emergency department visits between the two treatment modalities. These compelling findings incontrovertibly support the adoption of cryoablation as an efficacious and secure initial therapeutic approach for symptomatic AF. Nonetheless, it is imperative to diligently contemplate the aforementioned limitations while interpreting the findings. Subsequent investigations are warranted to authenticate these findings within larger, more heterogeneous patient cohorts and to explore the enduring effects and potential benefits of cryoablation in the management of AF.

The lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

CF is the corresponding author. QS and CF had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: QS and CF. Acquisition and interpretation of data: QS, CF, HT and BY. Statistical analysis: QS, HL and CF. Drafting of the manuscript: QS, HT and BY. Critical revision of the manuscript for important intellectual content: CF and HL. Study supervision: CF. All authors have read, provided critical feedback on intellectual content and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

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This research received no external funding.

The authors declare no conflict of interest.