Main findings
Among published studies comparing the HPSD technique with the conventional approach, this is the first RCT using the incidence of periprocedural SCE as the primary outcome. The main findings are summarized as follows. (1) Despite detecting lesions using brain hDWI at a thickness of 1 mm, no significant differences were found in the incidence, average lesion number, maximum lesion diameter, and total lesion volume of SCE between patients in the HPSD group using the novel STSF catheter and the conventional group using the ST catheter. (2) Persistent AF and CHA2DS2-VASc score were identified as the main risk factors for the occurrence of SCE during the AF ablation procedure. (3) None of the patients with SCE showed cognitive impairment during the 3-month follow-up period.
Cerebral embolic lesions, reported up to 67.3% [
4], are the most common complications associated with AF ablation procedure. By utilizing the STSF catheter, the HPSD ablation strategy has been indicated to be associated with shorter ablation time, greater first-pass PVI, lower risk of acute and chronic PV reconnection, and reduced risk of AF recurrence after a single ablation procedure, with reliable procedural safety [
7‐
16]. However, the incidence of SCE or stroke during HPSD procedure has only been reported as a safety event in a few published studies [
9,
10,
21‐
23]. Meanwhile, published studies have indicated an association between the occurrence of SCE and the likelihood of cognitive impairment [
5,
6]. The question that, compared to the conventional approach using the ST catheter, whether the HPSD strategy using the STSF catheter would decrease the incidence of SCE and its potential impact on patients’ cognitive function has been repeatedly proposed by clinical doctors. Thus, to comprehensively assess the incidence of SCE during the HPSD procedure and its potential impact on patients’ cognitive function, we performed the present randomized study, with the primary outcome directly defined as the incidence of periprocedural SCE. Moreover, to depict the occurrence of SCE objectively and accurately, this study is the first application of the hDWI technique in clinical trials involving the HPSD ablation strategy. Finally, as shown in the present study, SCE events were identified in 22 patients (44%) in the HPSD group and in 20 patients (40%) in the conventional group, with no significant differences between the two groups. Furthermore, the detailed lesion characteristics such as maximum lesion diameter, average lesion number, and the total lesion volume were also thoroughly analyzed and compared, but no significant differences were found. Despite the fact that the procedure time and RF time were significantly shorter in the HPSD group, as well as the utilization of a novel 56-hole STSF catheter with a lower electrode–tissue interface temperature, the incidence of SCE was not effectively reduced in the HPSD group compared with the conventional group. Similar to the present study, Dr. Scaglione et al. [
24] conducted a randomized pilot study 10 years ago to investigate the brain safety of open-irrigated catheters with different irrigation designs during AF ablation procedures, including the Thermocool Surround Flow 56-hole catheter and the Thermocool 6-hole catheter. The pilot study enrolled 80 patients with paroxysmal AF and randomized them 1:1 to the Thermocool Surround Flow group or the Thermocool group [
24]. The authors also performed a cerebral MRI before and after the AF ablation procedure. Their results showed that two patients (5%) in the Thermocool Surround Flow group and three patients (7.5%) in the Thermocool group suffered from SCE, with no statistical difference between the two groups (
p = 0.500) [
24]. As the thickness of the cerebral MRI in the study by Dr. Scaglione et al. was 5 mm [
24], the reported incidence of SCE in the study was only 6.25% (5/80). To accurately display the occurrence of SCE during the AF ablation procedure, the cerebral MRI slice thickness was established at 1 mm in the present study. As a result, the incidence of SCE in the present study was up to 42% (42/100), which is significantly higher than that in the study by Dr. Scaglione et al. Furthermore, the detailed lesion characteristics, including maximum lesion diameter, average lesion number, and total lesion volume, were analyzed and compared in the present study, but no significant differences were found between the two groups. Thus, by using the hDWI method and performing the thorough analysis, the results of the present study were much more accurate and reliable. Additionally, in the study by Dr. Scaglione et al. [
24], the delivered power for both the Thermocool Surround Flow catheter and the Thermocool catheter was 30 W, increasing to 40 W only when atrial potentials failed to ablate. In contrast, the present study revealed the brain safety of the popular HPSD technique with the power setting at 50 W.
However, the results of recently published SHORT-AF study [
25] indicated a trend towards a higher incidence of acute SCE with the HPSD strategy (10 out of 25, 40%) compared to the conventional approach (5 out of 30, 17%), without reaching statistical significance (
p = 0.053). It is worth noting that the primary objective between the SHORT-AF study and the present study is completely different. The SHORT-AF study was designed as an RCT to test the hypothesis that HPSD resulted in a shorter procedure than SPSD without compromising efficacy or safety [
25]. Thus, the primary outcome of the SHORT-AF study was defined as time to achieve PVI, while the incidence of acute SCE was just defined as one of the secondary safety endpoints [
25]. In contrast, the present study is the first RCT in which the primary objective was to comprehensively assess the incidence of SCE during the HPSD procedure. Correspondingly, the primary outcome of the present study was the incidence of new SCE detected by post-procedural hDWI within the 24–72 h after ablation. Additionally, the aims and assumptions for sample size calculations between the two studies are also completely different. The sample size of 60 patients in the SHORT-AF study was determined to detect a 17-min difference in PVI time between the two groups, but not calculated to detect the difference in the incidence of acute SCE between the two groups [
25]. Given that the conclusion about a trend toward a higher incidence of acute SCE for patients in the HPSD group was drawn from the secondary safety endpoints of the SHORT-AF study, the interpretation of this finding should be approached with caution and be verified in future randomized studies. In contrast, the sample size of 100 patients in the present Reduce-IT study was calculated to directly detect the difference in the incidence of acute SCE between the HPSD group and the conventional group. However, regarding the findings of these two studies, the revealed incidence of acute SCE for patients in the HPSD group appeared comparable, with 40% (10/25) in the SHORT-AF study [
25] and 44% (22/50) in the present Reduce-IT study. Notably, despite utilizing a similar high-resolution MRI technique, the SHORT-AF study reported a 17% (5/30) incidence of acute SCE for its conventional group [
25]. That is significantly lower than the 40% (20/50) in the present Reduce-IT study and the 67.3% (37/50) from a previously published study [
4]. Based on above discussion, the reported trend of an increased risk of acute SCE with the HPSD strategy, coupled with the notably lower incidence of acute SCE for the conventional group in the SHORT-AF study, could be potentially attributed to its limited sample size. Additionally, in the SHORT-AF study, both the HPSD and conventional groups underwent AF ablation procedures using either the CARTO or EnSite system, each employing distinct catheter designs [
25]. Such variations, compounded by the small sample size lacking statistical evaluation, intensified the heterogeneity and instability in the findings of secondary safety endpoints, such as the incidence of acute SCE. Therefore, the findings of the SHORT-AF study, regarding a trend towards a higher incidence of acute SCE with the HPSD strategy based on secondary endpoints, should be interpreted with caution and verified in future randomized studies. Interestingly, the present randomized Reduce-IT study seemingly just further investigated and addressed the concerns raised by the SHORT-AF study regarding the trend towards a higher incidence of acute SCE with the HPSD strategy. Furthermore, the detailed lesion characteristics such as maximum lesion diameter, average lesion number, and the total lesion volume were also thoroughly analyzed and compared in the present study, but still no significant differences were found.
Up to 42 enrolled patients (42%) had SCE in the present study. Although catheter ablation without anticoagulant interruption is recommended at a class I level [
1,
2], the minimally interrupted oral anticoagulants approach with holding one to two doses of DOAC before AF ablation procedure is recommended as reasonable (class IIa) by the AF catheter ablation expert consensus [
26] during the protocol design stage of the present study. Thus, the minimally interrupted oral anticoagulants approach was employed in the present study. We acknowledged that omitting the oral anticoagulants on the morning of the ablation day may have increased the occurrence risk of SCE [
27]. However, a randomized study conducted in Japan [
28], which enrolled 846 Asian patients, showed that both the uninterrupted and minimally interrupted protocols demonstrated a low risk of symptomatic thromboembolisms and a similar incidence of silent cerebral ischemic lesions. Meanwhile, the periprocedural anticoagulation management protocol is similar for all enrolled patients, regardless of whether they are in the HPSD group or the conventional group. Correspondingly, the risk of SCE from omitting anticoagulation on the ablation day was equal for patients in both groups. To investigate the risk factors for SCE during the AF ablation procedure, clinical characteristics and procedural parameters were compared between patients with and without SCE. Univariable and backward stepwise multivariable regression analyses were further performed. The results showed that persistent AF and CHA
2DS
2-VASc score were the main risk factors for SCE during the AF ablation procedure. We can easily find that the identified risk factors of persistent AF and CHA
2DS
2-VASc score were both the patient-level variables but not the procedure-related factors. As shown by the univariable regression analysis, procedural parameters of ablation with PVI plus strategy and procedure time were potential risk factors for SCE, but were excluded from the equation of multivariable regression analyses. These results indicate that the weight of the patient-related factors of persistent AF and CHA
2DS
2-VASc score in the occurrence of SCE during AF ablation procedure is substantially higher than that of ablation with PVI plus strategy and procedure time, although these two procedural parameters were also associated with the risk of SCE. However, the interpretation of this finding should be cautious. The previous study conducted in Chinese patients using the hDWI method already indicated that a procedural parameter of ACT > 283 S was an independent factor in lessening the risk of SCE during AF ablation procedures [
4]. In the present study, the median ACT before energy delivery was up to 292.0 S in patients with SCE and 299.5 S in patients without SCE (
p = 0.572), while the median mean ACT during the procedure was also up to 288.5 S in patients with SCE and 296.0 S in patients without SCE (
p = 0.227). Thus, we propose that the effective management of procedural anticoagulation in the present study plays a critical role in reducing the risk of procedural parameters in the occurrence of SCE and should be considered as a prerequisite for interpreting the findings.
As previously discussed, patient-related characteristics of persistent AF and CHA
2DS
2-VASc score were subsequently identified as the most relevant risk factors for SCE during AF ablation procedure, after procedural anticoagulation management was improved to reduce the procedure-related risk of SCE. Previous non-randomized studies had also shown that the patient-related characteristics of persistent AF [
29‐
31] and CHA
2DS
2-VASc score [
32,
33] were the main predictors of SCE during AF ablation procedure. There’s no doubt that patients with a higher CHA
2DS
2-VASc score have a higher prevalence of cardiovascular risk factors and diseases, such as heart failure, hypertension, older age, diabetes, stroke, and vascular disease. Consequently, these patients are more likely to develop persistent AF [
1,
34]. Meanwhile, patients with persistent AF and a higher CHA
2DS
2-VASc score are more likely to have a markedly enlarged left atrium as a result of the atrial remodeling process [
1,
34,
35]. Left atrial contractility is notably diminished in patients with persistent AF and an enlarged left atrium [
35,
36]. Accordingly, the blood flow velocity in the left atrium is also significantly reduced [
35‐
37]. As a result, during the delivery of RF energy, there is a dramatic increase in the risk of thrombus and char formation, which are the crucial mechanisms contributing to the occurrence of SCE during AF ablation procedures [
38‐
40]. Meanwhile, published study has indicated that most microemboli are gaseous in nature and are generated immediately after RF energy delivery [
41]. As such, even with intensive procedural anticoagulation management, the risk of char formation, thrombus development, and gaseous microemboli resulting from RF energy delivery is unavoidable, especially in patients with persistent AF or a significantly enlarged left atrium. Additionally, in patients with persistent AF, the performance of PVI plus strategy and cardioversion during the ablation procedure also increases the risk of SCE, as these two factors were identified as risk factors by univariable analysis but were excluded from the equation of the multivariable regression analysis after the variables of persistent AF and CHA
2DS
2-VASc score were introduced. As shown in Table
5 of the present study, the incidence of SCE is 56.1% (23/41) in patients with persistent AF and 32.2% (19/59) in patients with paroxysmal AF. Thus, based on the above discussion, it is easy to understand that patient-related characteristics of persistent AF and CHA
2DS
2-VASc score were identified as the most relevant risk factors for SCE during AF ablation procedure.
In the present study, 106 lesions in 42 patients were identified by hDWI after ablation, but none of the patients exhibited clinical symptoms. Meanwhile, no significant cognitive decline was detected in SCE patients by the MoCA test during the 3-month follow-up. Of the 106 lesions identified, 53 (50%) were small (< 3 mm), 52 (49%) were medium (3 mm ≤ diameter < 10 mm), and only one (1%) was large (≥ 10 mm). In a study conducted by Dr. Deneke et al. [
42], 50 acute lesions in 14 AF patients were identified by post-ablation cerebral MRI. Similar to the present study, up to 94% of the acute cerebral lesions were small or medium in size, while only 6% had a diameter greater than 10 mm [
42]. Another study by Dr. Zheng et al. [
33] also showed that more than 90% of the acute cerebral lesions after AF ablation were small to medium in size (< 10 mm). Meanwhile, previous studies have shown that all small- and medium-sized acute lesions disappeared during the 2–4-week MRI follow-up, while only the large acute lesions with diameters greater than 10 mm developed into the chronic cerebral infarcts [
30,
31,
42,
43]. Consistent with the present study, Dr. Deneke et al. [
42] and Dr. Haeusler et al. [
43] also reported no association between the occurrence of SCE after AF ablation and cognitive impairment. To date, no AF ablation study has found a direct association between post-ablation SCE and adverse neuropsychological outcomes, although Dr. Gaita et al. [
44] reported that patients with paroxysmal and persistent AF had a higher prevalence of SCE and poorer cognitive performance than subjects in sinus rhythm.