Just as “You can’t judge a book by its cover”...

“You can’t judge a book by its cover” is a saying that we likely have all heard. It suggests that the title of a written work is misleading with respect to the plot or message of the story contained within. The Catcher in the Rye, [1] A Clockwork Orange, [2]. To Kill a Mockingbird [3] are all classical book titles that might fit into this category. So, too, is the title of a manuscript by Tingqiong Ma et al. presented in this issue of IJC Heart & Vasculature −- Is Nifekalant More Effective Than Amiodarone in Improving the Clinical Outcomes of Catheter Ablation in Patients with Persistent Atrial Fibrillation? [4].

In brief, the Ma paper describes a retrospective observational explorative study in 300 patients who underwent radiofrequency catheter ablation (CA) for persistent atrial fibrillation (Per-AF) in which ablation did not terminate the AF. Those patients were then given either intravenous nifekalant (N) or intravenous amiodarone (A). Importantly, the choice of drug was determined by the procedurist rather than by randomization and the groups had notable demographic differences, including a longer AF history and larger left atria in the N group, as well as fewer patients in the N group (n = 121) than the A group (n = 179). Outcome results were compared in two propensity matched subgroups (n = 101 for each). Amiodarone was given as 5 mg/kg while N was given as 0.3 mg/kg –each over 5–20 min. In the group given N, 12 (11.88 %) converted to sinus rhythm (SR), as compared to 4 (3.96 %) given A and 45 (44.56 %) converted to an atrial tachycardia (AT), as compared to 15 (14.85 %). For patients remaining in AF, electrical conversion under anesthesia was performed and the procedure was terminated whereas those who converted to SR or AT underwent additional “targeted ablation” (which was longer and more extensive in the AT group than in the SR group). Follow-up (at 3, 6, and 12 months) included a 12-lead ECG, Holter monitor recording, and phone assessment of symptoms. Long-term success was higher for the N than the A treated patients at each time point and was higher for those patients who converted to SR or AT as compared to the entire study population. Effectiveness was especially greater for elderly patients with PeAF, a longer disease course, significant left atrial enlargement, lower LVEF, and concomitant hypertension in the N versus A group.

Given the above, we can now examine why the paper’s title is misleading. The title asks whether N is more effective than A in improving the clinical outcomes of CA in patients with Per-AF. The recurrence data above might appear to suggest that it is. However, appearances are not always what they seem at first glance. (1) Nifekalant is a class III antiarrhythmic drug that inhibits the Ikr channel with no beta blocker actions and no notable effect on sodium or calcium channels. It is approved in Japan for the treatment of life-threatening ventricular tachyarrhythmias (VT/VF) [5]. While to my knowledge it has not been approved in other countries, N has been studied in some, including in China, for VT/VF, for suppression of bypass tracts, and for the termination of atrial flutter and fibrillation (including AF post ablation). In its AF studies , doses of 0.4 and 0.5 mg/kg have had higher rates of cardioversion than 0.3 mg/kg, [6], [7] the dose used by Ma et al, though with more side effects. Amiodarone, whose history and uses are extensive and likely require no elaboration here, has also been used for the termination of AF in many circumstances. However, the A doses most commonly described for AF are notably higher than the dose used in the Ma paper (5 mg/kg). Accordingly, although the dosing studied by the authors may reflect their pattern in China, its relevance may be rather limited. (2) The more extensive ablation in the patients who converted to AT versus to SR, with the higher number of patients on N converting to AT than those given A, likely plays a significant role in the lower recurrence rates reported in the N versus A group. There is no pharmacologically plausible reason for a short acting intravenous drug given once to directly mediate a reduction in long-term AF recurrences. More likely, more ablation results in lower recurrence rates via a procedural effect and the drug given is of note only in that the high conversion rates to AT on N allowed for more potential ablation target sites to pursue. (3) The propensity-matching used by Ma included all baseline characteristics of the patients, including sex, age, height, weight, BMI, medical history, duration of AF, echocardiographic and electrocardiographic parameters. However, this is likely suboptimal [8] since it does not cover all factors that can affect ablation success or recurrence rates. Moreover, the pre-ablation demographic data provided in the paper is somewhat limited and there is essentially none in the post-ablation period. Notably absent is the prior and post ablation use of antiarrhythmic drugs and other concomitant therapies that may alter the development/recurrence of AF. Thus, again, how can differences in long-term recurrences be simply attributed to the use of N versus A during ablation. Along the same lines, the post ablation protocol for assessing recurrences is far from ideal [9]. It is well known that recurrence rates post ablation increase as the duration and continuity of monitoring increases and that the percentage of recurrences that are asymptomatic is higher in post-ablation patients than pre-ablation. Thus, one can and should question whether assessment by phone calls, and periodic ECGs and Holter monitoring actually gives meaningfully accurate information regarding actual AF recurrences post ablation [9]. Accordingly, the long-term recurrence rates in this study must be taken as perhaps rough estimates at best. That having been said, the Ma et al. study does allow some specific useful conclusions: (1) N is better than A for quickly converting AF; (2) N allows more conversion to AT and hence more extensive ablation which facilitates long-term outcomes; and (3) N dosing and safety evaluations need more information, especially in other populations in larger prospective trials.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.