Author + information
- aThe Northern Hospital, Epping Victoria, Australia
- bUniversity of Western Ontario, Schulich School of Medicine, London, Ontario, Canada
- ↵∗Address for correspondence:
Dr. Manoj N. Obeyesekere, Arrhythmia Service, The Northern Hospital, Cooper Street, Epping, Victoria NA 3076, Australia.
Management of the asymptomatic patient with pre-excitation continues to be controversial. In this issue of JACC: Clinical Electrophysiology, Etheridge et al. (1) provide a collaborative retrospective case-control study from 6 countries and 22 centers, spanning 25 years. The paper reinforces established knowledge that invasive electrophysiological study (EPS) variables are imperfect at identifying the higher-risk patient but, remarkably, also suggest that even identifying the low-risk patient to be problematic. Given this imprecision, a low threshold for catheter ablation is proposed in the current era of catheter ablation.
To address this, we discuss not only what the study supports but also what it does not address. Critically, the study does not address the incidence of sudden death in asymptomatic patients (i.e., the “denominator”) although it indirectly reinforces the rarity of sudden death by the very length of time it took multiple large tertiary pediatric centers to accumulate a small number of patients with catastrophic outcomes: an average of 4 patients per center over 25 years! (An estimate of the incidence is calculated below.) The study corroborates the limitations of EPS at identifying the at-risk patient but is not appropriately designed to evaluate the relative safety/efficacy of liberalized ablation versus a conservative strategy, as it is essentially a collection of patients with unfortunate outcomes, drawn from an unknown but arguably large pool of asymptomatic patients.
What Is the Relevant End Point in Evaluating Strategies For Asymptomatic Pre-Excitation?
Although debatable, no one would argue that the most relevant are death or significant long-term disability. Without these, it is probable that the controversy over this issue would be less intense. The authors report on 96 cases with life-threatening events (LTEs) gathered over a 25-year period, defined as sudden death (n = 6), aborted sudden death (n = 43), or a clinical episode of pre-excited atrial fibrillation (AF) (n = 47), either with a shortest pre-excited RR interval (SPERRI) of ≤250 ms or any pre-excited AF associated with hemodynamic compromise, syncope, or seizure. From these, the majority (85%) recovered completely. Thus, of 96 patients with LTE, 9 patients died, 5 had neurological injury, and the rest were treated without sequelae. One might then consider the number of patients to be treated in the wider pre-excited population to prevent these 14 outcomes.
Does Pre-Excitation Carry a High Incidence of Sudden Death?
This is really critical, as it informs the question of how aggressively one needs to seek out and manage this problem. The presented data allow some estimate: that is, 14 events over (96 × 14.3 years) + (816 × 13.4 years) (see Table 4 in the paper by Etheridge et al. ), a rate of 0.1% per year of death or neurological sequelae. This is surely an overestimate, accepting that it would be expected to be higher in this select population. The study enrolled 912 patients from 22 tertiary pediatric centers over a 25-year period, many from cities serving populations of millions. Even if one accepts the broader end point of LTE, 96 patients from such a huge population, over many years, is still miniscule. Pre-excitation has been estimated to cause sudden death in an astonishingly low 3.6 per 10 million person-years in the general population (2). The fundamental reality of a low event rate must be balanced with the risk of any management approach. Primary prevention cannot be completely informed by secondary prevention data derived from large, tertiary institutions serving large populations.
Assuming One Is Risk Stratifying, What Are the Critical Risk Stratifiers?
It is accepted that asymptomatic status does not preclude sudden death, which is especially relevant in children for whom the symptom status may be more difficult to elucidate if it were present. The challenges of predicting a rare event when the event rate is in the range of 0.1% per year is evident from the mathematics and should be well known to any clinical scientist. Thus, it is hardly surprising that a perfect risk stratifier has not been forthcoming. But that does not mean that every patient identified with pre-excitation should be ablated.
This study supports the supremacy of anterograde refractory properties as exemplified by SPERRI <250 ms, most specifically (Table 4, and Figure 3 in the paper by Etheridge et al. ). The problem remains the relatively nonspecific nature of this finding in that only a small number from natural history and prospective studies will go on to have a fatality, even with a SPERRI of <250 ms.
On the other hand, case reports of patients with moderate or long accessory pathway (AP) refractory parameters at EPS, who have had sudden death, are very rare. This study does not tell us how many patients who had sudden death or long-term neurological disability actually had a long AP effective refractory period (APERP)/SPERRI nor do the authors specifically provide the antegrade AP properties of the 9 patients who died.
The authors do report that LTE occurred in 22 with SPERRI/APERP/SPPCL >250 ms out of the 912 patients. Even accepting pre-excited AF as an outcome, this constitutes only 2.4% with no markers of high-risk (i.e., false negatives) and would be lower still if only death/neurological injury were used. Indeed, the authors arguably demonstrate high specificity (i.e., high true negative rates) (Figure 3 in the paper by Etheridge et al. ). Long-antegrade properties in the face of reported LTE in the relatively infrequent cases that occur may be related to sedation or anesthesia, potential contusion to the AP during insertion or manipulation of catheters, variability in autonomic tone, or the effects of concomitant medication. The data reporting a relatively small number of false negative results in patients from 22 large centers over 25 years do not challenge and arguably do support the general utility of markers of long AP refractoriness. The notion of ablating all patients with pre-excitation regardless of AP properties is, in our view, not supported and, it is hoped, not intended by the authors.
Should All Be Ablated?
If one does proceed to ablate all patients regardless of anterograde properties, the number to treat would indeed be very high. Even a pessimistic 0.1% annual mortality/neurological event rate would yield a number needed to ablate of 1,000 per year to prevent 1 death/neurological injury). Arguably, the risk of well-documented adverse effects from ablation in the “real world” would erode this potential low benefit. Indeed, this study from experienced tertiary centers reports a complication rate of 9% and an ablation failure rate of 18%. No ablation deaths occurred in this highly select population, although it would be unrealistic not to expect death or other potential lethal complication in some. Death has been reported as a complication of pediatric ablation due to cardiac perforation, myocardial trauma, coronary or cerebral thromboembolism, and ventricular arrhythmia (2). Recurrence of AP conduction can be as high as 24.2%, based on AP location (2). Highlighting the limitation that ablation is not a guaranteed cure, the authors themselves report a patient lost to follow-up presenting in ventricular fibrillation, having had a previous apparently successful AP ablation.
Should This Particular Study Change Our Practice?
The limitations notwithstanding, we interpret the data of this study as very much in line with the mainstream knowledge of managing patients with pre-excitation. The data reiterate the well-known fact that the asymptomatic patient is not immune from sudden arrhythmic death. The very small number of sudden deaths reported from large referral bases over many years underscores the very rare occurrence of sudden death due to pre-excitation in the studied population, undoubtedly rarer in the wider pre-excited population, and rarer still in the general population (2). These findings ought to reassure health care providers of the overall exceedingly low risk of devastating outcomes. The study also supports the general supremacy of anterograde conduction properties of the AP in assessing a patient even if it is not 100% infallible.
Ablation has advanced in both safety and efficacy over the years with a lowering of our threshold for ablation, but we would not be having this discussion if the ablation procedure were without risk while the risk of nonintervention was unreasonably high. Cost is also relevant, especially if one believes that we should be undertaking mass screening in addition to treating only those patients who present by serendipity.
Surely, our threshold for ablation will go down with further advances in safety and cost, but we are not at that point yet. Until then, reasonably informed patients may still wish to choose the management strategy on the basis of their views and individual considerations, with arguable equipoise between an expectant or proactive approach.
↵∗ Editorials published in JACC: Clinical Electrophysiology reflect the views of the authors and do not necessarily represent the views of JACC: Clinical Electrophysiology or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- 2018 American College of Cardiology Foundation
- Etheridge S.P.,
- Escudero C.A.,
- Blaufox A.D.,
- et al.
- Obeyesekere M.N.,
- Klein G.J.
- Corresponding Author
- What Is the Relevant End Point in Evaluating Strategies For Asymptomatic Pre-Excitation?
- Does Pre-Excitation Carry a High Incidence of Sudden Death?
- Assuming One Is Risk Stratifying, What Are the Critical Risk Stratifiers?
- Should All Be Ablated?
- Should This Particular Study Change Our Practice?