Development of an Improved End Point for Atrial Fibrillation Therapies: A Modified Atrial Fibrillation Burden Score to Account for Both Rhythm and Rate Control

EP Lab Digest. 2023;23(2):6.

Dear Readers,

The primary end point for most atrial fibrillation (AF) ablation trials has been the recurrence of any atrial arrhythmia lasting more than 30 seconds after a 3-month blanking period. Investigators and regulatory agencies have used this outcome for clinical trials of antiarrhythmic drugs and catheter ablation procedures for AF for years because it is an objective end point, it can handle variable follow-up durations, and allows for comparison to a control group and prior historical studies using the Kaplan-Meier survival analysis. However, use of this end point has come under increased scrutiny. Using AF recurrence as a primary outcome leads to patients with continuous AF who have a single recurrence of asymptomatic AF lasting only one minute on a monitor being considered as “failures”. The reality is that many of these patients are markedly improved clinically with substantial reductions in their AF burden. The time to recurrence approach fails to capture the true benefit of some AF interventions such as catheter ablation.

Quality of life (QOL) is another useful end point for clinical trials. Two studies on the impact of catheter ablation on QOL in patients with symptomatic AF were simultaneously published in 2019.^1,2 Tools used to measure QOL included the Atrial Fibrillation Effect on Quality of Life (AFEQT) summary score and the Mayo AF-Specific Symptom Inventory (MAFSI) frequency score in the CABANA trial, and the General Health subscale score (Medical Outcomes Study 36-Item Short-Form Health Survey) in the CAPTAF trial. Both studies showed that AF ablation improves QOL. These studies were important contributions, but using QOL scores derived from patient questionnaires as an outcome measure can only be done so often after an intervention and may be a relatively insensitive way to detect benefit from a procedure.

AF burden, measured as the percentage of time that a patient is in AF, has become a more commonly used metric to quantify the impact of AF on a patient, and is increasingly being used as an end point in AF management as well as clinical trials. One of the first large studies to use AF burden as an end point was the CIRCA-DOSE trial, led by Dr Jason Andrade.³ In this AF ablation trial comparing radiofrequency ablation to cryoballoon ablation, the primary end point was freedom from any atrial arrhythmia at 12 months, excluding a 3-month blanking period. The success rate based on recurrence rates was 52% in each group. However, the impact of ablation on arrhythmia burden was dramatic. The median reduction in AF burden compared to baseline in all groups was nearly 99%. Clearly, AF burden tells a more accurate story of the benefits of ablation for AF compared to time to AF recurrence.

A disadvantage of using AF burden as a metric is that its measurement requires continuous rhythm monitoring, typically with an implantable loop recorder or other cardiac implantable electrical device (CIED), and requires intensive data collection and analysis. Another limitation is that it does not account for rate control during AF. For example, it is likely that a patient with an AF burden of 20% whose average heart rate (HR) increases from 60 beats per minute (bpm) during sinus rhythm (SR) to 120 bpm during AF might be far more symptomatic from, and negatively impacted by, their AF compared to a patient with the same AF burden of 20% whose average HR only increases from 60-70 bpm. A substudy of CAPTAF looked at the HR during AF as a factor driving symptoms in patients with AF.⁴ Although they found that a median HR greater than 110 bpm during AF was not predictive of QOL, they only considered HR during AF as a dichotomous variable and did not consider the difference between the HR during AF and during SR. A comprehensive metric for patients with AF that accounts for the degree of both ventricular rate control and rhythm control may be a better metric than AF burden alone. A modified AF burden defined as the AF burden x (average HR in AF/average HR in sinus) adjusts the %AF burden to a score that accounts for how well their rate is controlled during AF. The modified AF burden can be calculated readily using data from ambulatory monitor reports or a CIED. This novel metric accounts for both AF rhythm and rate control, and may be a useful efficacy measure of AF therapies.

AF ablation and drug trials are increasingly using AF burden and QOL as primary and secondary outcomes. Future studies are needed to determine if a patient’s modified AF burden, which captures both rhythm and rate control, correlates better than AF burden alone with AF-related symptoms, QOL, hospitalizations, and other clinically relevant end points. 

Disclosures: Dr Knight has served as a paid consultant to AltaThera, manufacturer of IV sotalol. He has also served as a paid consultant to Medtronic, the sponsor of the EV ICD study, served on the EV ICD Steering Committee, and was an investigator in the trial. In addition, he has served as a consultant, speaker, investigator, and/or has received EP fellowship grant support from Abbott, AtriCure, Baylis Medical, Biosense Webster, Biotronik, Boston Scientific, CVRx, Medtronic, Philips, and Sanofi; he has no equity or ownership in any of these companies.

References

1. Mark DB, Anstrom KJ, Sheng S, et al. Effect of catheter ablation vs medical therapy on quality of life among patients with atrial fibrillation: the CABANA randomized clinical trial. JAMA. 2019;321(13):1275-1285. doi:10.1001/jama.2019.0692

2. Blomström-Lundqvist C, Gizurarson S, Schwieler J, et al. Effect of catheter ablation vs antiarrhythmic medication on quality of life in patients with atrial fibrillation: the CAPTAF randomized clinical trial. JAMA. 2019;321(11):1059-1068. doi:10.1001/jama.2019.0335

3. Andrade JG, Champagne J, Dubuc M, et al. Cryoballoon or radiofrequency ablation for atrial fibrillation assessed by continuous monitoring: a randomized clinical trial. Circulation. 2019;140:1779-1788. doi:10.1161/CIRCULATIONAHA.119.042622

4. Jansson V, Bergfeldt L, Schwieler J, et al. Atrial fibrillation burden, episode duration and frequency in relation to quality of life in patients with implantable cardiac monitor. Int J Cardiol Heart  Vasc. 2021;34:100791. doi:10.1016/j.ijcha.2021.100791