• Catheter ablation of paroxysmal AF aiming at electrical pulmonary vein isolation (PVI) as first line therapy resulted in maintenance of sinus rhythm in drug naïve patients.

• Cryoballoon Catheter Ablation was superior to antiarrhythmic drug (AAD) therapy, significantly reducing Atrial tachycardia recurrence in treatment-naive patients with symptomatic paroxysmal atrial fibrillation.

• Catheter ablation was associated with a similar adverse risk profile as compared to antiarrhythmic drug therapy.

Atrial Fibrillation is the most common cardiac arrhythmia encountered in clinical practice. It is associated with increased morbidity, mortality, and impaired quality of life [1]. It is frequently recurrent and follows a progressive course over time [2]. Current guidelines recommend the use of antiarrhythmic drugs (AAD) as initial therapy for AF and before catheter ablation (CA) is considered [3]. However, antiarrhythmic drugs have limited efficacy and are associated with adverse effects [4].

Multiple randomized controlled trials (RCTs) have shown that CA is superior and safe than AAD in maintaining sinus rhythm and preventing recurrent arrhythmias [5, 6, 7, 8, 9, 10, 11, 12]. CA has also demonstrated improvement in left ventricular ejection fraction (LVEF) and quality of life compared to AAD pharmacotherapy in patients with heart failure [13, 14, 15, 16].

In clinical practice, patients with symptomatic refractory AF or those intolerant to AADs undergo CA. This is mainly preceded by the failure of AADs [17]. However, accumulating evidence has suggested that early ablation in AF with shorter diagnosis-to-ablation times allows better rhythm control [18, 19, 20]. Similarly, the recent Early Treatment of Atrial Fibrillation for Stroke Prevention Trial (EAST-AFNET 4) showed that early rhythm control results in better clinical outcomes than standard care management [21]. To date, only a few studies have investigated the role of CA as a first-line therapeutic modality for AF patients [22, 23, 24, 25, 26, 27]. Whether early CA halts AF progression or is associated with improved clinical outcomes remains unclear. The best appropriate timing for ablation in patients with symptomatic AF, regardless of AF type, has not been determined.

Considering recent evidence regarding this matter [25, 26, 27], a systematic review and meta-analysis was performed to examine the safety and efficacy of CA vs AAD as first-line treatment for the maintenance of sinus rhythm in symptomatic AF patients.

The initial search yielded 6881 results, of which 5231 articles were screened for title and abstract. Consequently, records were removed due to ineligibility (reviews, editorials, non RCTs, ongoing trials, and abstracts). The search strategy is shown in Fig. 1. A full-text screening of 17 articles led to the inclusion of 6 studies, with 1212 participants (609 patients in the CA group and 603 patients in the AAD group) [22, 23, 24, 25, 26, 27]. Quality assessment findings of the included studies are summarized in Supplementary Figs. 1,2.

4.2 Clinical Outcomes

4.2.1 Primary Efficacy Endpoint

Five out of six studies reported the recurrence of any atrial tachyarrhythmia (Symptomatic/Asymptomatic; AF, Atrial flutter, atrial tachycardia) [22, 23, 24, 25, 26]. Recurrence occurred in 160 of 577 (27.7%) patients who underwent CA and 223 of 457 (45%) patients on AAD. Our meta-analysis revealed a 37% reduction in the risk of recurrence of any type of atrial tachyarrhythmia (RR 0.63; 95% CI 0.55–0.73; p 0.00001) with no heterogeneity among studies I${}^2$ = 0 (Fig. 2).

Fig. 2.

Forrest plot comparing the primary efficacy endpoint of catheter ablation to antiarrhythmic drug therapy as first line treatment for atrial fibrillation.

Cryoablation as an ablation procedure was evaluated in three recent studies. There was a 40% reduction in the risk of recurrence of any types of atrial tachyarrhythmia (RR 0.60 95% CI 0.50–0.72; p 0.00001) with no heterogeneity among the studies (I${}^2$ = 0) (Fig. 3).

Fig. 3.

Forrest plot comparing the primary efficacy endpoint of cryoablation to antiarrhythmic drug therapy as first line treatment for atrial fibrillation.

4.2.2 Secondary Efficacy Endpoint

4.2.2.1 Recurrence of Symptomatic Atrial Tachyarrhythmia

Four out of five studies reported recurrence of symptomatic Atrial Tachyarrhythmia [22, 23, 24, 25]. A secondary outcome of symptomatic recurrence of AF, atrial flutter or atrial tachyarrhythmia was reported in 83 patients of 398 patients (20.8%) in the CA group compared with 141 (35.8%) in the ablation group. A better response was observed in the CA group with a 47% reduction in the risk of recurrence of symptomatic atrial tachyarrhythmia (RR 0.53; 95% CI 0.32–0.87; p = 0.01). There was moderately high heterogeneity among the studies included for the analysis (I${}^2$ = 71%) (Fig. 4).

Fig. 4.

Forrest plot comparing catheter ablation to antiarrhythmic drug therapy (as first line treatment for atrial fibrillation) for the recurrence of symptomatic tachyarrhythmia.

4.2.2.2 Quality of Life (QoL)

QoL was reported only in three of the six included studies. It was measured by using the 36-item Short Form General Health Survey (SF-36) in 1 study [22] and European Quality of Life 5 Dimension (EQ-5D) in 2 studies [24, 25]. The study that used SF-36 reported an improvement in QoL both in the physical and mental domains in patients who underwent CA. A significant improvement (WMD 11 95% CI 8–12; p 0.001) was observed in general health at a six-month follow-up visit. Similar improvement was observed in the other two studies that used EQ-5D to assess QoL. These results could not be compared because different measurements were used to evaluate QoL parameters.

4.2.2.3 Safety-Adverse Events

All six studies reported the overall adverse effects after treatment and were included in the meta-analyses [22, 23, 24, 25, 26, 27]. The details of adverse events are described in Supplementary Table 1. The number of adverse events were 111 of 609 (18.2%) patients who underwent CA and 124 of 603 (20.5%) patients who were on AAD. However, there was no significant difference in the incidence of major adverse events between ablation and AAD (RR 0.93; 95% CI 0.68–1.27; p = 0.64) with homogenous findings (I${}^2$ = 36%) (Fig. 5).

Fig. 5.

Forrest plot comparing catheter ablation to antiarrhythmic drug therapy (as first line treatment for atrial fibrillation) for the incidence of adverse events.

4.2.2.4 Cardiovascular Adverse Events

The cardiovascular events have been described in Supplementary Table 2. Out of 609 patients in the ablation arm and 603 patients in the AAD arm, 61 (10%) and 75 (7.9%) experienced cardiovascular events, respectively. Using a random-effects model, we determined that the catheter ablation group had similar odds as compared to the AAD group in experience cardiovascular adverse events (RR 0.90; 95% CI 0.56–1.44; p = 0.65), with no heterogeneity among studies (I${}^2$ = 43%) (Fig. 6).

Fig. 6.

Forrest plot comparing catheter ablation to antiarrhythmic drug therapy (as first line treatment for atrial fibrillation) for the incidence of cardiovascular adverse events.

On visual assessment, the funnel plot was symmetrical with an equal number of studies on each side of the vertical axis. There was no publication bias demonstrated. Egger’s test for the assessment of publication bias was non-significant (2-tailed p $>$ 0.05) (Supplementary Figs. 3,4,5,6,7).

This meta-analysis of six RCTs, including 1212 patients, compares the CA’s efficacy and safety outcomes as first-line therapy versus AAD in symptomatic AF patients. The main findings of this meta-analysis are as follows: (i) CA (Cryoballoon or Radiofrequency- Pulmonary vein Isolation) resulted in a significantly lower rate of any recurrent atrial tachyarrhythmias when used in antiarrhythmic naïve patients. (ii) This effect was observed irrespective of follow-up duration (short versus long term), and type of catheter ablation (radiofrequency versus cryoablation). (iii) CA was not associated with an increase in the rates of overall severe adverse events and cardiovascular adverse events; while procedural adverse events included tamponade, pulmonary stenosis and pericardial effusion.

To our knowledge, this is the first comprehensive meta-analysis to compare clinical outcomes of CA versus AAD as first-line therapy for symptomatic AF and included the results of the recent EARLY-AF, STOP-AF First and Cryo-FIRST trials [25, 26, 27]. A prior meta-analysis from 2015 explored the impact of CA and AAD as initial therapy but was underpowered due to paucity of data and a limited number of included studies [32]. In addition to exploring more endpoints, the current study is the first to include both radiofrequency and cryoballoon studies to compare CA and AAD as first-line treatments for AF.

Radiofrequency ablation (RFA) and cryoballoon ablation (CBA) are both safe and effective options for treating atrial fibrillation. In a recent meta-analysis comparing RFA and CBA, there were no statistically significant differences between the two energy sources regarding AF/atrial tachycardia-free survival and overall adverse events [33]. CBA has emerged as a promising alternative with comparable efficacy to RF ablation for the maintenance of sinus rhythm, primarily in patients with paroxysmal AF. Triggers originating from the pulmonary and thoracic veins appear to be the primary mechanism of subjects with paroxysmal AF [34]. Extending the role of CBA aiming at the electrical pulmonary vein as a novel catheter ablation strategy, the current study supports the use of CBA as initial first-line therapy, like that observed with radiofrequency ablation. These findings from the current meta-analysis are in concordance with the recent EARLY-AF, STOP-AF First and Cryo-FIRST trials [25, 26, 27].

Although more successful than AAD, most ablations in clinical practice are performed in patients who fail AAD due to either inefficacy or side effects [17]. However, this conventional “standard of care” consisting of the first attempt of rhythm control with AAD may represent a delay in an optimal treatment. Drug therapy often fails due to adverse events and arrhythmia breakthroughs, and the time that passes between AAD introduction and failure can cause a delay in time-to-ablation, during which progressive electro-anatomical remodeling may render AF more refractory. A shorter diagnosis-to-ablation time has been associated with better ablation outcomes [18, 19, 20]. Similarly, a prior study from our center showed that markers of atrial remodeling such as hemodynamic strain and inflammation progress with longer diagnosis-to-ablation times in persistent AF.

Furthermore, the longer diagnosis-to-ablation time has been associated with worse AF-related outcomes such as heart failure and death [35]. In the progressive course of AF, atrial scarring and fibrosis can occur, reducing the ability to maintain sinus rhythm as observed in the DECAAF trial [36]. Finally, the ARISTOTLE trial showed a higher risk of stroke at advanced stages in AF progression [37], which further supports earlier ablative intervention; but this requires further investigation. This data and the current findings suggest implications for the timing of early aggressive management of AF and its favorable impact on disease progression. Moreover, progression of AF is less common with CA intervention than AAD therapy [35, 36, 37]. Therefore, CA provides the most significant benefit earlier in the disease.

Many patients are given AAD first in clinical practice, owing to concerns with the invasive nature of catheter ablation. In the current study, the incidence of both overall adverse events and cardiovascular adverse events including ischemic and embolic events (myocardial infarction, stroke, or transient ischemic attack), hospitalizations for heart failure, major bleeding, pulmonary vein stenosis, pericardial complications (effusion, hemorrhage, tamponade, and perforation), syncope, and life-threatening arrhythmias were similar in both CA and AAD groups. The ability of CA procedures to obviate the need for AAD long term may inherently avoid the risks associated with long term use of antiarrhythmics.

Although AADs are not benign, invasive procedures and long-term radiation exposure are similar risks to medical therapy. Complications were reported in 9.35% patients and included pericardial tamponade/effusion (1.8%), symptomatic pulmonary vein stenosis (0.67%), bleeding complications (0.5%), and phrenic nerve injuries (0.5%). Cardiac tamponade was the most common fatal complication of AF ablation, occurring in seven of 609 patients. Supplementary Table 2 summarizes the common complications occurring during CA of AF. The operator’s experience is critical regarding safety issues of catheter ablation of AF. Moreover, most reported adverse events occurred after 30 days. However, the safety profile for procedural risks is excellent, especially at tertiary care centers with experienced operators. CA should be done carefully after weighing the benefits and risks of the procedure.

Several limitations of our study should be acknowledged. The definition of outcomes varied substantially among the included studies. This analysis included studies that differed in the use of Class I or III AADs, types of AF and method of surveillance used to monitor recurrence, with the follow-up period varying from 1–2 years. Five studies included patients with paroxysmal AF, and hence the data is only relevant to patients with paroxysmal AF and should not be extrapolated to patients with persistent AF. This meta-analysis combines the different ablation techniques (RFA and Cryoballoon) to evaluate the primary efficacy endpoints, thereby adding a new dimension to the study while presenting as a limitation.

Furthermore, ablation targets beyond the pulmonary veins are variable and mostly up to operators’ preferences. However, the primary efficacy endpoint was consistent in the ablation arm across all studies. The study has the strength of compiling RCT and confirming the superiority of ablation vs AAD to prevent arrhythmia recurrences without significant risks.

In this study, comparing the efficacy and safety of catheter ablation (RFA and CBA) and antiarrhythmic drugs as first-line therapy for symptomatic AF, catheter ablation aiming at electrical pulmonary vein resulted in a significantly lower recurrence rate of atrial tachyarrhythmia and maintenance of sinus rhythm. Catheter ablation for AF rhythm control is superior to AAD in drug naïve patients.

AAR—Conception of the study, drafting, editing, reviewing, and final approval of the study to be submitted. HML—Help in the design of the study, drafting, editing, reviewing, and final approval of the study to be submitted. SP—Drafting, editing, and final approval of the study to be submitted. SR—Drafting, editing, and final approval of the study to be submitted. SAH—Drafting, editing, and final approval of the study to be submitted. NH—Drafting, editing, and final approval of the study to be submitted. HN—Drafting, editing, and final approval of the study to be submitted. KTR—Drafting, editing, and final approval of the study to be submitted. HS—Drafting, editing, and final approval of the study to be submitted. FY—Drafting, editing, and final approval of the study to be submitted. AM—Drafting, editing, and final approval of the study to be submitted. SC—Drafting, editing, and final approval of the study to be submitted. MBM—Critical revision of the manuscript, editing, reviewing, and final approval of the study to be submitted. AFB—Critical revision of the manuscript, editing, reviewing, and final approval of the study to be submitted.WS—Critical revision of the manuscript, editing, reviewing, and final approval of the study to be submitted. OW—Critical revision of the manuscript, editing, reviewing, and final approval of the study to be submitted. AAH—Critical revision of the manuscript, editing, reviewing, and final approval of the study to be submitted.

Not applicable.

We acknowledge the patients, their referring clinicians, and the brave front-liners that continue to risk their lives to save others.

This research received no external funding.

Oussama Wazni serves a consultant speaker for Boston Scientific and Biosense Webster. The remaining authors have no conflict of interest.