Who Benefits Most From Early Rhythm Control in Newly Diagnosed Atrial Fibrillation?

Abstract

HomeCirculationVol. 146, No. 11Who Benefits Most From Early Rhythm Control in Newly Diagnosed Atrial Fibrillation? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBWho Benefits Most From Early Rhythm Control in Newly Diagnosed Atrial Fibrillation? Eunice Yang, MD, PhD and Hugh Calkins, MD Eunice YangEunice Yang Division of Cardiology, Inova Heart and Vascular Institute, Falls Church, VA (E.Y.). Search for more papers by this author and Hugh CalkinsHugh Calkins Correspondence to: Hugh Calkins, MD, Johns Hopkins Hospital, 1800 Orleans St, Sheikh Zayed Tower, Room 7125R, Baltimore, MD 21287-0409. Email E-mail Address: [email protected] https://orcid.org/0000-0002-9262-9433 Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (E.Y., H.C.). Search for more papers by this author Originally published12 Sep 2022https://doi.org/10.1161/CIRCULATIONAHA.122.060945Circulation. 2022;146:848–850This article is a commentary on the followingEarly Rhythm Control in Patients With Atrial Fibrillation and High Comorbidity BurdenAtrial fibrillation (AF) serves as an independent predictor of decreased quality of life, morbidity, and mortality in select patient populations.1 As the most common arrhythmia, AF affects an estimated 46.3 million individuals worldwide, and diagnoses of new AF have become increasingly frequent owing to improved public health awareness and enhanced detection from ambulatory electrocardiographic monitoring.2,3 The medical field has met the growing AF population with the creation and refinement of the armamentarium of AF therapies. In the wake of increasing numbers of patients with AF and treatment options, there is an imperative need for studies to guide the selection of appropriate treatments within this vastly heterogeneous patient population.Article, see p 836Management of AF has traditionally focused on mitigating thromboembolic risk with systemic anticoagulation and determining the need for rate versus rhythm control as a quality-of-life intervention. This treatment paradigm was guided by historic studies, including the landmark AFFIRM trial (Atrial Fibrillation Follow-Up Investigation of Sinus Rhythm Management), which reported no difference in rate versus rhythm control in risk for all-cause mortality, cardiovascular hospitalization, or ischemic stroke.4 However, since AFFIRM was published in 2002, various studies have established AF as a considerable risk factor for poor clinical outcomes extending well beyond thromboembolic risk: AF has been associated with the development of heart failure,5 myocardial infarction,6 dementia,7 and overall mortality in select populations.8–10The premise of cumulative AF burden over time driving some of these expanded clinical sequelae has spurred reinvestigation of benefits of rhythm control. The EAST-AFNET4 study (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial 4) was one of the critical players in this reinvestigation, addressing the question all of the electrophysiology community has asked in the wake of our improving rhythm control armamentarium: Are the risks afforded by AF modifiable, particularly if we intervene in a timely fashion? Who might benefit from this treatment?In contrast to historic trials, the EAST-AFNET4 study demonstrated superiority of early rhythm control over rate control in patients with recent-onset AF.11 The EAST-AFNET4 study has been met with overwhelming enthusiasm by the electrophysiology community in underscoring the clinical impact made by pursuing early rhythm control in AF. An overall benefit for pursuing early rhythm control having been demonstrated, the next step was to investigate which participants benefitted most from early intervention.In this issue of Circulation, Rillig and colleagues12 assessed the impact of early rhythm control on study participants stratified by the presence of a high burden of cardiovascular comorbidities. This was a prespecified subanalysis of the EAST-AFNET4 study. They used the CHA2DS2-VASc score to identify individuals with high and low cardiovascular comorbidities, using a cutoff CHA2DS2-VASc score ≥4 for individuals with high comorbidity burden. Individuals with high CHA2DS2-VASc scores assigned to early rhythm control were significantly less likely than their counterparts with high CHA2DS2-VASc scores assigned to usual care to experience one of the composite outcome events, which included cardiovascular death, stroke, or hospitalization for worsening heart failure or acute coronary syndrome. This benefit did not extend to those in the CHA2DS2-VASc score <4 subgroup, with significant interaction noted from the CHA2DS2-VASc subgroup designation on the impact of early rhythm control on composite efficacy outcomes. In contrast, the healthier subgroup (CHA2DS2-VASc score <4) was initially shown to have a significantly higher risk for developing adverse safety events when assigned to the early rhythm control arm, whereas this difference was not seen in those with a CHA2DS2-VASc score ≥4. Sensitivity analysis performed with removal of sex designation revealed robust clinical efficacy findings in the high CHA2DS2-VASc score subgroup receiving early rhythm control but did not reinforce safety concerns in terms of adverse safety events in the low CHA2DS2-VASc score subgroup undergoing early rhythm control. This loss of significance occurred despite increasing power, with more women reassigned from the high to the low CHA2DS2-VASc score subgroup. Although only a small fraction of individuals pursuing rhythm control underwent AF ablation, it is important to note that female sex has previously been associated with an increased risk of complications after radiofrequency ablation procedures.13 Elimination of sex in the CHA2DS2-VASc designation also rendered the interaction term in clinical efficacy outcomes insignificant. These findings all serve to highlight that the contribution of sex to cardiovascular outcomes may be more nuanced than what would be reflected in the traditional CHA2DS2-VASc score. Female sex certainly plays a contributing role in adverse cardiovascular outcomes in the AF population, but whether it serves as a traditional risk factor or as an effect modifier as some have surmised14 remains to be more thoroughly investigated.The findings reported by Rillig and colleagues challenge current practice patterns and take a stance in support of early rhythm control in individuals carrying cardiovascular comorbidities. However, the reported benefit of early rhythm control merits a closer look to see what potential components may drive the reported outcome. First, when we look at each component from the composite outcomes, we notice a strikingly discrepant incidence of thromboembolic events in the high CHA2DS2-VASc score subgroup, with the usual care arm having more than twice the risk of developing stroke than the early rhythm control arm (7.9% versus 3.5%; hazard ratio, 2.33 [95% CI, 1.35–4.00]; P=0.002, Pinteraction=0.021). This finding is a major driver of the reported efficacy outcome and is present despite what we would assume to be good adherence to systemic anticoagulation in both the early rhythm control and usual care treatment arms under a highly controlled study setting.Second, taking a closer look at the subgroup comorbidities, we see that nearly half of all the individuals with high CHA2DS2-VASc scores have heart failure. Given the previously reported EAST-AFNET4 analysis of the benefits of early rhythm control in heart failure,15 it is reasonable to wonder how much of the benefit seen in the high CHA2DS2-VASc score subgroup was driven by benefit in individuals with heart failure. If this group were removed, would the remaining group see clinical benefit from early rhythm control, or would these findings be eliminated by the potential adverse safety outcomes? There is certainly a need to highlight other potential groups who may benefit from early rhythm control interventions, but the stratification design of this study does not provide the granularity with which we can do so.Last, although EAST-AFNET4 has focused on early rhythm control, the predominant strategy with which rhythm control is achieved is antiarrhythmic medications, with just 8% of all participants assigned to the early rhythm control arm receiving ablation as first-line therapy at baseline, increasing to just under 20% receiving AF ablation by the 24-month follow-up. We suspect that a major driver of the composite safety outcomes reported in individuals with low CHA2DS2-VASc score may arise from antiarrhythmic drug side effects, which have been well highlighted in previous historic studies. What remains to be learned, then, is whether there is benefit from rhythm control using ablation in this relatively healthy population diagnosed with AF and whether the benefit from ablation can extend to other individuals with more cardiovascular comorbidities.In conclusion, Rillig and colleagues have put forth a study that challenges our traditional AF management paradigm, arguing that sicker individuals with more cardiovascular comorbidities may actually benefit from more aggressive rhythm control interventions. Our read of their analysis is that if a patient’s CHA2DS2-VASc score is high, it is possible that the clinical benefit afforded by early initiation of antiarrhythmic medications may outweigh the possible adverse events seen with these medications. It would certainly be interesting to see future studies dedicated to investigating the benefit of ablative management of AF in all types of patients with AF, and we will still need this information to help guide the selection of patients who will benefit the most from early ablative and nonablative rhythm control. As we await further studies to answer these questions, we have used the results of the EAST-AFNET4 trial to motivate early rhythm control for patients whose clinical profile is similar to that of the EAST-AFNET4 patient population. Our clinical experience alone has convinced us of the benefits of a rhythm control strategy for almost all patients with AF, and EAST-AFNET4 has provided us with the scientific justification we were certain would appear in due time.Article InformationSources of FundingNone.Disclosures Dr Calkins is a consultant for and/or has received honoraria from Medtronic, Atricure, Boston Scientific, Abbott, Biosense Webster, and Sanofi. Dr Yang reports no conflicts.FootnotesCirculation is available at www.ahajournals.org/journal/circThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 850.Correspondence to: Hugh Calkins, MD, Johns Hopkins Hospital, 1800 Orleans St, Sheikh Zayed Tower, Room 7125R, Baltimore, MD 21287-0409. Email [email protected]edu