This study is the first randomized trial that compares rhythm and rate control strategies in treatment of persistent atrial fibrillation dedicated to patients with CRT—a specific population in which AF treatment may have a direct influence on their heart failure treatment (mediated by the CRTs BiVp% increase). To the best of authors’ knowledge, it is the first attempt to fill in, at least partially, the gaps in evidence on the efficacy of CRT in persistent AF patients, which are still listed in the latest ESC guidelines [6, 13].

Regardless of the fact that both of the treatment strategies resulted in similar and marked increase of BiVp% exceeding 95%, an increase of LVEF was observed only in the rhythm control group and it was restricted to patients who maintained sinus rhythm through the whole follow-up.

There may be at least two reasons for the lack of effectiveness of the rate control strategy observed in our study.

The first one is that although high, the BiVp% in this group was not high enough. Such hypothesis seems to be reasonable in view of the APAF-CRT study results in which CRT implantation and AVNA in patients with heart failure and persistent atrial fibrillation lasting more than 6 months has led to mortality reduction and lower risk for HF hospitalizations and had to be stopped prematurely for efficacy [15]. However, it should be underlined that the APAF-CRT study population differed significantly from the one observed in our study. Contrary to Pilot-CRAfT patients, the APAF-CRT population comprised of patients that did not met standard CRT criteria (narrow QRS + and at least one hospitalization for heart failure irrespective of the ejection fraction). According to large observational studies of Hayes [10] and Ousdigian [11], the BiVp% cutoff value which guarantees the best effectiveness of CRT (resulting in the biggest mortality reduction) is > 98%. Indeed, 71% of patients from the RHYTHM group (and 87.5% of those who had SR at 12 months) had BiVp ≥ 98% in comparison to only 56% of patients with BiVp ≥ 98% in the RATE group. However, the observational works of Tolosana, dedicated to patients with BiVp reduction associated with permanent atrial fibrillation suggest that no additional effect in further BiVp% increase above 90–95% is observed, irrespective of the fact whether patients were in SR or had the ventricular rate controlled by drugs or by AVNA [16, 17]. As a result, the current ESC Guidelines on Cardiac Pacing suggest performing AVNA only in patients with BiVp lower than > 90–95% [6]. It has been shown that CRT effectiveness starts to rise beginning with the values of BiVp% exceeding 90% [10, 11], so the evident increase of BiVp% in the RATE control group in our study should have had a positive influence on the factors assessed.

Another possible explanation for a better outcome of the rhythm control may be a positive effect of sinus rhythm maintenance itself, irrespective of the BiVp%. This hypothesis is supported by the fact that LVEF rise was restricted predominantly to patients who maintained sinus rhythm during whole follow-up period. A significant rise in LVEF after sinus rhythm restoration suggest the presence of arrhythmia/atrial fibrillation-mediated cardiomyopathy (AMC) in this group of patients. AMC concerning further deterioration of LV function and exacerbation of HF symptoms related to the occurrence of arrhythmia/atrial fibrillation in patients with already impaired LV function due to underlying structural heart disease remains still an underestimated, potentially reversible cause of HF exacerbation. Indeed, successful elimination of arrhythmia in AMC patients leads increase of LVEF as it was shown in the CAMERA-MRI study and the improvement of in the quality of life [18, 19]. Sinus rhythm control may positively affect the prognosis of patients with HF as it was proven in the CASTLE-AF, the AMICA and, recently, in the CASTLE HTx trials [20,21,22,23]. What is important, the rhythm control strategy implemented in the aforementioned trials was characterized by significant percentage of AF relapses proving limited efficacy in maintaining sinus rhythm in the HF patients’ population as it was shown in our study. In the AMICA trial, a sinus rhythm was observed in 73.5% of patients in the ablation group and 50% in the best medical therapy group after 12 months of the follow-up. Even greater number of AF relapses was observed in rhythm control arm of the CASTLE HTx trial—the lack of AF was observed only in 5% of the ablation group after 1 year of follow-up, even though the AF burden was significantly reduced in the ablation group suggesting that it is more AF burden reduction than a complete AF elimination that has prognostic effect in the HF patients.

Contrary to our study, CRT patients constituted the minority in the CASTLE-AF, AMICA and CATLE-HTx trials. However, the similarity of our study results with these of AMICA suggests that the beneficial effect of sinus rhythm maintenance in HF patients is comparable between CRT and non-CRT patients.

Although beneficial, rhythm control was achieved in a very limited number of the study participants. The main reason for that may be a very long duration of AF in our group. Other factors limiting the efficacy of antiarrhythmic treatment in our study were the participants’ age, serious LA enlargement and serious LVEF impairment that were all generally more advanced in comparison to both the CASTLE-AF and the AMICA trials [21, 22].

Recently, new forms of cardiac resynchronization that is: left bundle branch area pacing (LBBAP) and left bundle branch-optimized cardiac resynchronization (LOT-CRT) have emerged becoming a potential alternative to the standard biventricular CRT [24, 25]. However, their ability in overcoming interventricular conduction abnormalities is still inherently connected with the amount of effectively captured paced beats, making the results of our study potentially applicable in LBBAP and LOT-CRT-treated patients with AF as well.

The main limitation of the study is a low number of participants. Though, interpretation of the study secondary end-points’ results should be regarded as hypothesis generating. In order to improve the enrollment rate, the Steering Committee of the trial decided to prolong the enrollment phase, invited another high-volume center and changed the minimal duration of current AF paroxysms from at least 1 year to 6 months. Regardless of these measures, the study did not reach the prespecified number of 27 participants in each study arm [14].

The study population consisted of vast majority of males (97%) which makes interpolation of our results to women population impossible.

Another limitation is a heterogeneity within the strategies applied, while only small number of patients from the RATE group underwent AVNA and PVI CA was rarely performed in the RHYTHM group. The reason for rare AVNA use was that in majority of RATE patients, BiVpace > 95% was achieved with drugs only. As it comes to pulmonary vein isolation, it was not offered to many patients due to their unfavorable characteristics hindering ablation efficacy (discussed above). It has to be underlined that the vast majority of patients were followed up before the publication of CASTLE-AF and the subsequent trials, which led to a broader use of CA in severe HF patients. Nevertheless, a more strict protocol may have diminished heterogeneity in the groups.

We examined BiVp% values assessed by CRT devices, which may be artificially higher than the real effectively captured BiVp beats percentage due to the inability to rule out fusion and pseudo-fusion beats [7]. However, we routinely switched-off algorithms that trigger LV pacing after RV sensed beats, which was not the case in the studies of Tolosana and could lead to overestimation of BiVp% in their no-AVN ablation group [16, 17].