Atrial fibrillation ablation alone or atrial fibrillation ablation plus an antiarrhythmic drug?

This editorial refers to ‘PulmOnary vein isolation With vs. without continued antiarrhythmic Drug trEatment in subjects with Recurrent Atrial Fibrillation (POWDER AF): results from a multicentre randomized trial’†, by M. Duytschaever et al., on page 1429. Atrial fibrillation (AF) is the most common cardiac arrhythmia in the world, with ∼1 in 4 people of European descent developing AF over their lifetime after the age of 40 years.1 A trigger is required to induce AF, and abnormal atrial substrate is needed in order to maintain AF. The majority of triggers for AF originate in the pulmonary veins,2 which is why electrical isolation of the pulmonary veins is the recommended (class IA) and most common ablation strategy for AF.3 There is evidence that AF ablation improves quality of life and may improve ejection fraction in patients with heart failure with reduced ejection fraction; however, the data on the impact of AF ablation on mortality and stroke remain inconclusive.3 Prospective, randomized trials among patients having failed at least one antiarrhythmic drug (AAD), including the THERMOCOOL investigational device exemption (IDE) and the Sustained Treatment of Paroxysmal Atrial Fibrillation (STOP-AF) trials, demonstrated that AF ablation has better freedom from AF recurrence (66% and 70% at 9 and 12 months, respectively) than AAD therapy (16% and 7% at 9 and 12 months, respectively).4 , 5 Catheter ablation for paroxysmal AF has a class IA guideline recommendation in patients who have symptomatic AF despite attempted AAD therapy.3 , 6 However, there has been limited available data on optimal strategies for AAD therapy, especially after the post-ablation blanking period (Take home figure). Factors associated with and protective against recurrence of atrial fibrillation. Multiple other clinical trials of AF ablation vs. AAD therapy allowed the use of antiarrhythmic medications during a blanking period in the ablation arms of the trials; however, long-term antiarrhythmic medication use beyond a blanking period was discouraged in these trials.7–9 A European survey of AF ablation practice that included 1300 patients from 72 European institutions found that among a patient population that was more than two-thirds paroxysmal AF, 65% of patients were discharged post-ablation on an antiarrhythmic medication; 49% and 40% remained on antiarrhythmic medication at 12 months and after 12 months post-ablation, respectively.10 A small randomized study found that AAD use in the 90-day ‘blanking period’ cut a composite endpoint (AF >24 h, cardioversion, admission, or significant drug side effect) in half.11 Using administrative data, Noseworthy et al. found that initiation of an AAD after AF ablation reduced the 90-day readmission rate by 37%, but only amiodarone was statistically significant when looked at individually. Moreover, many patients stopped the drug even during this short interval, perhaps related to side effects.12 The Efficacy of Antiarrhythmic Drugs Short-Term Use After Catheter Ablation for Atrial Fibrillation (EAST-AF) trial evaluated the use of a blanking period AAD in patients who had undergone AF ablation for paroxysmal or persistent AF.13 While taking the AAD, post-ablation patients were less likely to experience recurrent AF. However, after stopping the AAD at 90 days, there was no carryover effect; the incidence of recurrent AF was nearly identical at 1 year in the two groups. In other words, there was no positive feedback loop appreciated, i.e. sinus rhythm did not beget sinus rhythm. Most of the data support suppression of AF in the blanking period by AAD.11–13 Would a longer duration of AAD post-AF ablation (beyond 90 days) continue to suppress AF effectively throughout the year, or is the effect better during the blanking period? Would this suppression change the natural history of recurrence, an effect not seen with 90-day use? In this issue of the European Heart Journal, Duytschaever et al. present POWDER-AF, an unblinded, open-label randomized controlled trial evaluating the 1-year outcomes of using previously ineffective AAD therapy continued beyond the 3-month blanking period for pulmonary vein isolation in patients with paroxysmal AF.14 There were 153 patients randomized (76 in the no AAD therapy cohort and 77 in the AAD therapy cohort) at three institutions. Use of AAD therapy beyond the blanking period resulted in a markedly lower rate of repeat ablation at 1 year (1.4% vs. 19.2%, P < 0.01), which was consistent with the 88.9% (95% confidence interval 51.5–97.4%) lower hazard of atrial tachyarrhythmias. Similarly, the cohort that continued AAD therapy had a lower rate of unscheduled arrhythmia-related visits at 1 year (2.7% vs. 20.5%, P < 0.01). Symptom severity scores and quality of life scores at 3, 6, and 12 months were statistically similar in patients who were randomized to continuing vs. stopping AAD therapy after the blanking period. Among patients treated with continued AAD therapy, left atrial size <40 mm was associated with lower recurrence of atrial tachyarrhythmias, relative to patients with left atrial size ≥40 mm (P-value for interaction 0.023). Within the AAD therapy cohort, 6 (10.2%) of the 72 patients who were free from atrial tachyarrhythmias at 12 months post-ablation stopped their AAD therapy due to adverse events. The investigators of POWDER-AF should be commended, as the study had many strengths, including the importance of the clinical question, the use of contact force ablation, and the fact that only 2 out of 160 patients approached for trial participation declined. However, the clinical implications of this study need to be considered within the context of several limitations. First, the trial consisted of a highly selected patient population, which may not be representative of the overall AF ablation patient population. This is demonstrated by the fact that 907 (84%) of the 1077 patients who underwent AF ablation at the study sites during the trial period did not fit the inclusion/exclusion criteria for the trial. Furthermore, only 9% of patients in the trial had structural heart disease. These characteristics meaningfully differ from those of the US Medicare patients (n = 15,423) who had an AF ablation between mid-2007 and the end of 2009, in which 26% of patients had heart failure and 51% had ischaemic heart disease.15 Secondly, although the patients in the post-blanking period AAD therapy vs. no AAD therapy arms were well matched on median age (63 vs. 62 years), median AF history (26 vs. 26 months), and mean left atrial diameter (41 vs. 41mm), the relatively low number of patients in the trial could have resulted in an imbalance in baseline characteristics associated with long-term risk of AF recurrence between the two cohorts. For example, the patients without long-term AAD therapy had an older age at the 75th percentile (70 vs. 63 years) and were more likely to have at least one episode daily of AF (13% vs. 9%), a CHA2DS2-VASc score >2 (20% vs. 16%), and hypertension (43% vs. 30%). Also, the proportion of patients with sleep apnoea in each cohort was unknown. Thirdly, since a portion of the follow-up monitoring was investigator driven, the lack of blinding may have affected the intensity of screening for and thus the subsequent identification of AF recurrence. Finally, as the authors mentioned in the manuscript, the follow-up from the trial was too short to provide insight into long-term outcomes, as the primary endpoint was evaluated at 1 year. Multiple studies have shown that even among patients free of AF at 12 months and who are not taking an antiarrhythmic medication, the recurrence rates of AF are ∼25% at 5 years.3 , 16 It remains unclear how effective a previously failed AAD therapy would be in the long term, following AF ablation or whether the maintenance of long term sinus rhythm would be durable if AAD therapy were stopped at 1 year. It also is unknown if waiting to start an antiarrhythmic medication post-ablation until patients had AF recurrence would yield similar results to POWDER-AF. The European Survey of AF ablation practice found that only 31% of patients undergoing AF ablation were having the procedure done in order to eliminate medications, while 93% were focused on improving their symptoms.10 One noteworthy finding from the trial was that there was no difference in symptom frequency or symptom severity, raising the important question of whether or not freedom from >30 s of AF recurrence is the optimal endpoint for AF-related trials. The symptom scoring also has the potential to be more affected by bias from the study being unblinded, relative to outcomes such as AF recurrence or AF burden. It would have been helpful to know the symptom frequency and severity scores prior to ablation for the patients in the trial, as this may have provided greater insight into the interpretation of the symptom findings. The symptom checklist consisted of 16 questions with frequency rated 0–4 and severity rated 0–3; higher scores were consistent with more frequent and severe symptoms.17 Given that symptom frequency and severity scores ranged between 8 and 11, and 7 and 9, respectively, it may have been that the scores were already so low relative to pre-ablation scores that the measurement tool was not able to discern a difference in symptoms between the two cohorts. However, clinicians need to consider the net clinical benefit of continuing AAD therapy after the blanking period with lower rates of arrhythmia recurrence, repeat ablation, and unscheduled arrhythmia-related visits, despite no quantifiable improvement in symptoms and with 18% (n = 13/74) of patients in the AAD therapy cohort of the trial having medication-related adverse events. The trial did boast a nearly 20% absolute risk reduction (∼90% relative reduction) in AF recurrence. This reduction in AF recurrence needs to be placed in the context of other adjunctive therapies that have been studied in a post-AF ablation population. The Aggressive Risk Factor Reduction Study for Atrial Fibrillation and Implications for the Outcome of Ablation (ARREST-AF) cohort study was a non-randomized post-AF ablation study of paroxysmal and persistent AF patients who had risk factor modification for blood pressure, weight, lipids, diabetes, sleep-disordered breathing, smoking, and alcohol.18 Patients in the risk factor modification cohort had a >20% absolute lower 1-year single procedure AF-free survival and >30% lower 1-year multi-procedure AF-free survival. The intervention patients also had statistically lower symptom frequency and severity at follow-up.18 The POWDER-AF trial importantly highlights that the long-term use of AAD therapy post-ablation is one of the tools in our AF management armamentarium. Questions remain, including the following. (i) What happens after 1 year? (ii) Is the AAD suppression algorithm in POWDER-AF essentially trading AF symptoms for AAD side effects? (iii) Would reinitiation of AAD after recurrence work as well? Post-ablation recurrence of AF is undoubtedly multifactorial, with various factors operating in a time-dependent manner (Take home figure). Further research is needed on opportunities to impact the factors affecting AF recurrence and thus improve the quality of rhythm control after AF ablation.