4. Discussion
The main finding from our updated study that includes contemporary ablation tools is that catheter ablation for pulmonary vein isolation is more effective than AAD as initial therapy for pAF in reducing AT recurrences after the initial blanking period to 1-2 years. In addition, this benefit with ablation was the same in both cryoablation and radiofrequency ablation with similar relative reductions in risks. Despite the augmented efficacy for reduction in AF recurrences with catheter ablation, we did not observe a significant increase in any adverse events in these patients compared to AAD therapy.
In this updated meta-analysis of RCTs, we found two recently published RCTs that add to prior summary work in this area. The new search resulted in a total of 5 RCTs to date. The 2 newly added RCTs, EARLY-AF and STOP AF First, used cryoballoon ablation for pulmonary vein isolation, which is different from the previous 3 RCTs that all used radiofrequency ablation. Evidence from the Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation (FIRE AND ICE) trial suggested that treatment efficacy of cryoballoon ablation was non-inferior to the more traditional radiofrequency ablation in drug-refractory pAF [22]. However, the efficacy of cryoablation in treatment-naïve pAF was still unclear, especially when compared directly to AAD or radiofrequency ablation. The EARLY-AF trial and the STOP AF First trial were the first RCTs to compare cryoablation to AAD as an initial therapy for pAF. This gave us opportunity to indirectly compare the two ablation strategies as initial treatment for pAF. As shown in figure 1, the pooled HR for the cryoablation subgroup (figure 1A) was similar to the pooled HR for the radiofrequency ablation subgroup (figure 2). However, as these pooled data are derived from a retrospective comparison, further prospective RCTs that directly comparing the two techniques are needed to confirm this finding or investigate if one may be preferable over the other for treatment naïve pAF compared to AAD.
The included studies in our meta-analysis demonstrated a significant reduction in AT recurrence at 1-2 years with a similar effect size. The EARLY-AF trial and the RAAFT-2 trial reported HRs for AT recurrence. In the MANTRA-PAF trial, the RAAFT-1 trial, and the STOP-AF First trial, the authors did not report HRs for AT recurrence. Nevertheless, the authors provided sufficient raw data for us to calculate HRs as described in the methods section. The HRs from each study are shown in figure 1 along with the pooled HR.
The study designs are similar among the 5 included RCTs. Inclusion and major exclusion criteria are shown in table 1. Briefly, all studies included strictly symptomatic pAF without prior use of class I and III AADs. Major exclusion criteria being used in all studies were previous ablation or surgery of the left atrium, reversible causes of AF, structural or valvular heart disease, a left atrial diameter >5-5.5 cm, a left ventricular ejection fraction <35-45%, NYHA class III-IV heart failure. For AT outcome measurements, all studies reported using a blanking period of 60-90 days following the ablation with follow up of patients up to 1-2 years. Three studies used radiofrequency ablation and two studies used cryoablation as described in table 1. The subgroup analysis by ablation method is shown in figure 2A and 2B that demonstrates similar results between the 2 ablation techniques. The consistency and similarity in study design likely contributed to the absence of heterogeneity (I=0.0%) in our analysis, which indicates that our result is robust.
Atrial arrhythmia type as endpoint differs slightly among the included studies. The MANTRA-PAF trial and the RAAFT-1 trial considered only AF as the clinical endpoint for recurrence. For the EARLY-AF trial, the RAAFT-2 trial, and the STOP AF First trial, authors consider either of AF, atrial flutter, and atrial tachycardia as the clinical endpoint. It is likely due to the difference in definition of endpoint that the MANTRA-PAF trial and the RAAFT-1 trial reported lower recurrence rates than the other 3 RCTs, except for the AAD group from the RAAFT-1 trial that had a comparable recurrent rate to the other 3 RCTs.
Table 3 shows a summary of the adverse events. Overall, the adverse event rates were low, and not many specific adverse events of interest occurring in either of the ablation group or AAD group in some studies. We were able to perform a meta-analysis on several adverse events including cerebrovascular accident, PV stenosis, pericardial effusion or tamponade, bradycardia requiring pacemaker, syncope, acute coronary syndrome, DVT or PE, all of which were statistically similar between the two groups. For other adverse events including mortality, phrenic nerve injury, esophageal-related complications, and perforation, there was only 1 study available for a meta-analysis for each outcome. The individual ORs for these adverse events also did not demonstrate significant differences between the two groups. Nevertheless, these findings must be interpreted with caution as this could be from inadequate power from the extremely low number of events which subjects this sub-analysis to risk of a type II error.