To burn or to freeze: a burning question yet to be resolved

This editorial refers to ‘Cryoballoon or radiofrequency ablation for symptomatic paroxysmal atrial fibrillation: reintervention, rehospitalization, and quality-of-life outcomes in the FIRE AND ICE trial’ † , by K.-H. Kuck et al. on page 2858. Recently, the FIRE AND ICE Trial comparing cryoballoon ablation and radiofrequency catheter ablation (RFCA) in patients with symptomatic, drug-refractory paroxysmal atrial fibrillation (AF) was reported. 1 This was a randomized controlled non-inferiority trial with the primacy efficacy endpoint of time to first documented recurrent AF or atrial tachycardia (AT), prescription of antiarrhythmic drugs (AADs), or repeat ablation after a 90-day blanking period. 2 After a mean follow-up of 1.5 years, non-inferiority of cryoballoon ablation was confirmed; the two treatments did not differ with respect to either efficacy or overall safety (a composite of all-cause death, all-cause cerebrovascular events, and serious treatment-related adverse events). 1 In the current issue of the journal, the authors publish some of the secondary endpoints from the FIRE AND ICE trial, 3 namely all-cause and cardiovascular rehospitalizations, repeat ablations, direct current cardioversions, and quality of life. These are indeed important endpoints to report, addressing both the healthcare burden of an intervention and the patients’ perception of success. Cryoballoon ablation performed significantly better in reducing all-cause and cardiovascular rehospitalizations, including repeat ablations and direct current cardioversions, whereas there was no difference in improving quality of life. However, these findings raise some questions. For cardiovascular rehospitalizations, AF/AT recurrence was the main event driving the difference between groups. Why were these marked differences not accompanied by any alterations in the primary efficacy endpoint of arrhythmia control between the two groups? The primary efficacy endpoint was a composite endpoint that also included AT/AF recurrence/AAD prescriptions that did not result in rehospitalizations or repeat ablations. This analysis takes into account only those AT/AF recurrences that resulted in rehospitalizations. Therefore, one can infer that patients after RFCA are more symptomatic, requiring more cardioversions or repeat ablation compared with simple AAD prescription. However, it is important to note that this study also included events occurring in the blanking period. Considering the time-to-event curves and plots depicting events during follow-up, the difference in direct current cardioversions between groups was probably not significant beyond the blanking period. Similarly, for both all-cause and cardiovascular rehospitalizations, a larger difference in events occurred during the blanking period ( Figure 1 ). Do the differences between groups mainly reflect a difference during the first 90 days? This might be explained by a heightened inflammatory response after RFCA, with consequent more frequent early recurrences, which did not appear to influence later clinical outcomes in this cohort. Another explanation could be a lower prevalence of persistent pulmonary vein (PV) isolation in this group. On one hand, operators in the participating centres were more familiar with cryoballoon ablation, and contact force was employed only in one-third of RFCA procedures. Moreover, there was no direction regarding maintenance of a contact force range, and power was delivered up to 30 W in the posterior wall and roof and 40 W in the anterior aspect of the PVs, without any mention of contact force-guided power titration. Lastly, no drug challenge (adenosine or isoproterenol) was employed after ablation—which has been proven useful with RFCA. 4 It is also important to highlight that the study protocol specified that arrhythmia-related events during the blanking period would not be counted towards the primary endpoints. 2 Therefore, this being an unblinded study, a potential bias may have affected the results as regards the decision on the type of intervention (AAD, cardioversion, or repeat ablation). Events during follow-up (top) and time to event curves for the endpoint of cardiovascular hospitalization after the blanking period of 90 days. Redrawn from Kuck et al.3 . RFC, radiofrequency catheter. Another puzzling result is the difference in major bleeding events between groups. It is not easy to find a plausible explanation for it, and no clear definition for major bleeding is given. It does not appear to be related to a different rate in cardiac tamponades, also considering that adverse events occurring during the index hospitalization (such as cardiac perforation-related tamponades) should not be included in this analysis. In the original FIRE AND ICE trial, it was noted that a higher number of groin complications occurred in the RFCA group. The authors explained it by the double femoral puncture, compared with the single puncture required for cryoballoon ablation. First, it is important to note that the use of ultrasound to guide access would have prevented this complication to begin with. Moreover, it is hard to believe that a bigger sheath did not lead to a similar rate of haematomas/psuedoaneurysm, unless some other confounding factor was not taken into account (for example, a difference in the prevalence of uninterrupted anticoagulation or obese people between the two groups). Thus, this may be just a random effect as it lacks plausibility. Finally, other major bleeding events that are not treatment related (such as intracranial or gastrointestinal hemorrhage), should not be considered. After all, this is an analysis of secondary endpoints, not all of which were pre-specified. While hypothesis-generating, post-hoc analysis of data from a randomized trial principally should not be considered conclusive and need to be further tested by a trial specifically set up to test this hypothesis. Conflict of interest: A.N. reports consulting fees from Janssen, Medtronic, St. Jude Medical, Boston Scientific, and Biosense Webster. J.C.N. reports no conflicts of interest.