Author + information
- Matthew R. Reynolds, MD, MSc∗ ()
- Division of Cardiology, Lahey Hospital & Medical Center, Burlington, Massachusetts
- Harvard Clinical Research Institute, Boston, Massachusetts
- ↵∗Reprint requests and correspondence:
Dr. Matthew R. Reynolds, Division of Cardiology, Lahey Hospital & Medical Center, 41 Mall Road, Burlington, Massachusetts 01805.
The first successful closed-chest defibrillation of a human was described by Zoll et al. (1) in 1956. Soon after, the utility of external cardioversion for nonlethal arrhythmias was explored (2) and would with time become a routine intervention in the treatment of atrial fibrillation (AF). The great majority of patients with AF who were treated with cardioversion in the original reports had a history of rheumatic mitral valve disease, such that a high risk of thromboembolic complications was well understood (3). To reduce this risk, patients with mitral stenosis undergoing cardioversion “were generally treated with anticoagulant drugs for three to four weeks” (3) beforehand. Eventually, this practice would be applied to all cardioversions for AF except those with a very short duration of arrhythmia.
Thus, anticoagulation practices surrounding cardioversion have, since the advent of the procedure, been empirical but based on a known risk of a serious complication. Nonetheless, the original approach was mechanistically validated by transesophageal echocardiography (TEE) studies in the 1990s (4,5), and moderately large case series have consistently shown that standard use of a vitamin K antagonist for 3 to 4 weeks before cardioversion (or shorter periods if preceded by a negative TEE) will result in thromboembolic rates of <1% within 30 days (6,7).
Three novel oral anticoagulant drugs (NOACs) have been approved for prevention of stroke in patients with AF over the past few years, each showing at least noninferiority to warfarin in overall rates of stroke or systemic embolism (8–10). Given the entrenched role of vitamin K antagonists in cardioversion, there has been understandable curiosity regarding the safety and effectiveness of NOACs in this setting.
In this issue of the Journal, Flaker et al. (11) make an important contribution to our limited but growing knowledge of this topic. Their report describes the outcomes of 743 cardioversions in 540 patients during the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. The patients had been enrolled in the trial for a mean of >6 months before their first cardioversion, and TEE was performed before cardioversion in ∼27% of cases with no thrombi observed. Although the investigators had the option to switch each patient to open-label warfarin for the cardioversion, patients remained on their blinded study drug 80% to 85% of the time.
The authors observed no strokes or embolic events within 30 days, regardless of the anticoagulant used. Myocardial infarction, major bleeding, and death occurred rarely within 30 days and did not differ between patients randomized to apixaban and those randomized to warfarin. Given that no strokes or systemic emboli occurred, it made no difference whether the data were analyzed in an intent-to-treat or on-treatment manner.
With this report from the ARISTOTLE trial, each of the major randomized trials of the currently approved NOACs has now reported on outcomes after cardioversion (in the case of ROCKET-AF [An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation], outcomes after either cardioversion or AF ablation were reported) (12,13). In all 3 cases, only a minority of patients enrolled in the trial ever had a cardioversion, with the largest experience of 1,983 procedures coming from the RE-LY (Randomized Evaluation of Long Term Anticoagulant Therapy) trial. This reflects the predominance of persistent/permanent AF in these study populations. In all 3 series, the 30-day incidence of stroke/systemic embolism was <1% and did not differ whether the patient was treated with an NOAC or a vitamin K antagonist.
The study from Flaker et al. (11) has a few minor limitations that do not significantly detract from the main findings. First, given the low expected event rate after cardioversion and the limited number of observed procedures, this analysis did not have sufficient statistical power to find a small difference in outcomes between the warfarin and apixaban groups, and no strict definition of noninferiority was proposed or met. Nonetheless, the reported experience was large enough to rule out any large difference in the safety of cardioversion with apixaban as compared with warfarin, and the results are certainly reassuring. Second, the data collection forms were either designed or interpreted in such a way that the authors could not be certain that all of the cardioversions recorded were actually performed for AF. This probably has no bearing on the primary endpoint, but the reported secondary endpoints may need to be interpreted with caution as a result.
What we have learned from the current study, as well as the RE-LY and ROCKET-AF trials, is that cardioversions performed in the carefully controlled setting of a phase 3 randomized controlled clinical trial are associated with a low risk of embolic complications that probably does not differ whether the patient is treated with warfarin or any of the NOACs. For patients who have been treated with an NOAC for months and seem reliable with respect to adherence, there would appear to be no justification for switching them to warfarin if a cardioversion is planned.
Where we still lack information is the common clinical scenario of a patient newly diagnosed with persistent AF, where a cardioversion is planned and the clinician and patient must choose between warfarin or 1 of the NOACs. Is apixaban more, less, or equally effective compared with warfarin in this circumstance? Should TEE be performed? Is 3 to 4 weeks of oral anticoagulation before cardioversion enough? The available data suggest that apixaban (or another NOAC) should be no less effective than warfarin for this purpose, but the available data do not provide definitive answers; thus, additional research in this area is needed. In the meantime, clinical practice, as it has since the 1960s, will have to remain based at least partly on our best judgment.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Reynolds has reported that he has no relationships relevant to the content of this paper to disclose.
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