Comparison between High-Power Short-Duration and Conventional Ablation Strategy in Atrial Fibrillation: An Updated Meta-Analysis

High-power short-duration (HPSD) setting during radiofrequency ablation has become an attempt to improve atrial fibrillation (AF) treatment outcomes. This study ought to compare the efficacy, safety, and effectiveness between HPSD and conventional settings. PubMed, Embase, and Cochrane Library were searched. Studies that compared HPSD and conventional radiofrequency ablation settings in AF patients were included while studies performed additional ablations on nonpulmonary vein targets without clear recording were excluded. Data were pooled with random-effect model. Efficacy endpoints include first-pass pulmonary vein isolation (PVI), acute pulmonary vein (PV) reconnection, free from AF, and free from atrial tachycardia (AT) during follow-up. Safety endpoints include esophagus injury rate and major complication rate. Effectiveness endpoints include complete PVI rate, total procedure time, PVI time, and PVI radiofrequency ablation (PVI RF) time. We included 22 studies with 3867 atrial fibrillation patients in total (2393 patients received HPSD radiofrequency ablation). Perioperatively, the HPSD group showed a higher first-pass PVI rate (risk ratio, RR = 1.10, P = 0.0001) and less acute PV reconnection rate (RR = 0.56, P = 0.0004) than the conventional group. During follow-up, free from AF (RR = 1.11, P = 0.16) or AT (RR = 1.06, P = 0.24) rate did not differ between HPSD and conventional groups 6-month postsurgery. However, the HPSD group showed both higher free from AF (RR = 1.17, P = 0.0003) and AT (RR = 1.11, P < 0.0001) rate than the conventional group 12-month postsurgery. The esophagus injury (RR = 0.99, P = 0.98) and major complications (RR = 0.76, P = 0.70) rates did not differ between the two groups. The HPSD group took shorter total procedure time (MD = −33.71 95% CI: -43.10 to -24.33, P < 0.00001), PVI time (MD = −21.60 95% CI: -25.00 to -18.21, P < 0.00001), and PVI RF time (MD = −13.72, 95% CI: -14.45 to -13.00, P < 0.00001) than conventional groups while complete procedure rate did not differ between two groups (RR = 1.00, P = 0.93). HPSD setting during AF radiofrequency ablation has better effectiveness, efficacy, and similar safety compared with the conventional setting.


Introduction
Radiofrequency catheter ablation has been proven to be an effective treatment for atrial fibrillation (AF). Pulmonary vein isolation (PVI), aiming at blocking pulmonary veins (PVs) generated ectopic current conduction into the left atrial, is the most important radiofrequency ablation (RFA) technique for treating AF [1,2]. PV reconnection was recog-nized as the major cause of AF recurrence after PVI and the failure of AF catheter ablation, which makes durable and transmural lesions formed during ablation critical to longterm successful PVI. Multiple factors were correlated with high-quality RFA lesions, including power, contact force (CF), radiofrequency ablation time to form each lesion, impedance drop, and ablation site temperature. Novel indices were brought out by coordinating the abovementioned factors, like ablation index (AI) or lesion size index (LSI), aiming at achieving better AF radiofrequency ablation outcomes [3][4][5][6].
Power, as one of the most easily manipulatable parameters during the procedure, drew the interest of researchers for a while. The first attempt of increasing RFA power to 45 W and shortening ablation time was launched in 2006 by Nilsson and his colleagues [7]. Since then, high-power short-duration (HPSD) as a novel RFA strategy has been broadly studied in both animal models and clinical cases. By increasing resistive heating in the lesion core and reducing the lesion area caused by conductive heating, HPSD strategy creates shallower but wider lesions in both in silico and animal models compared with the conventional technique or so-called lower-power longer-duration (LPLD) strategy [8,9]. Several meta-analyses about the efficacy of HPSD strategy have been conducted but provided different results. Higher free from or less recurrence of atrial tachycardia (AT)/atrial flutter in HPSD group has been reported in some literature, while others disagreed [10][11][12][13]. Additional ablations than PVI during RFA procedure were performed at operators' discretion for different patients, which usually included left atrial posterior wall box isolation, linear isolation, and tricuspid isthmus ablation. These additional ablations on non-PV targets could be one of the sources of heterogeneity but have been ignored by most existing researches. For this reason, we conducted this updated meta-analysis comparing the efficacy, safety, and effectiveness between the HPSD and conventional strategies. We added the most updated studies with more precise sorting approaches, like distinguishing PVI from additional ablations and pooling AF or AT recurrence data according to whether additional ablations were performed or not. Different subgroup analyses were also performed in this study to further explore the effect of power, integral parameters, and antiarrhythmic drugs on AF rhythm management.

Studies Selection.
Search has been conducted in PubMed, Embase, and Cochrane Library from inception to January 2022 with language limited to English. The keywords for searching included "atrial fibrillation," "radiofrequency ablation," "catheter ablation," and "power" with their MeSH terms or Emtree checked corresponding to different databases. Detailed searching strategies are available in Supplementary Table S1-S3. Further literature retrieval was performed by screening the reference list of included articles. Two authors independently performed searches, screened titles, abstracts, and full texts when needed. Disagreements were solved through consensus.
The inclusion criteria for this study are as follows: (1) patients have been diagnosed with nonvalvular AF and underwent RFA for the first time; (2) PVI was performed by catheter radiofrequency ablation; (3) randomized controlled trials, nonrandomized trials, and observational studies included both HPSD and conventional (or low-power long-duration) treatment groups; (4) studies with at least 3-month follow-up after RFA. The exclusion criteria for this study are as follows: (1) additional RFA than PVI was performed without detailed reports for each independent ablation procedure; (2) studies with equivocal design or results reported; (3) single-armed studies; and (4) animal studies, case reports, conference abstracts, or literature lacking endpoints of interest.
The endpoints of interest in this study are efficacy endpoints, safety endpoints, and effectiveness endpoints. Efficacy endpoints included first-pass PVI, acute PV reconnection, free from AF or AT 6, or 12 months postsurgery. Safety endpoints included esophageal injury and procedure-related major complications. More specifically, we defined major complications as a composite endpoint including phrenic nerve paralysis, cerebrovascular accident, transient ischemic attacks (TIA), cardiac perforations, pericardial tamponade, pericardial effusion, and death. Effectiveness endpoints included complete PV isolation rate, total procedure time, PVI time, and radiofrequency ablations time to complete PVI (PVI RF time). Notably, total procedure time was not extracted from studies that conducted both classical PVI and other ablations but without a clear record for each process.
Data referring study characteristics and endpoints of interest were extracted by two authors independently from included studies. Study characteristics include study design, patient baseline information, catheters used for ablation, indexes that guided ablation procedure like power, time, and contact force.
The quality of included studies was assessed with the Newcastle-Ottawa scale (NOS), and the quality of RCTs was assessed by RoB2 additionally [14]. This study was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [15]. The protocol for this systematic review and metaanalysis was registered on PROSPERO (CRD42021266106).

Statistical
Analysis. Continuous variables were presented as mean and standard deviation (SD) and pooled by the inverse variance method. Median and interquartile range (IQR) were converted into SD for further pooled analysis by estimation with the method presented by Luo et al. and Wan et al. [16,17]. Dichotomous variables were presented as risk ratios (RR) and pooled by the Mantel-Haenszel method. The 95% confidence interval (CI) was used in both continuous and dichotomous data while two-sided P value of <0.05 was considered as statistically significant. The random-effect model instead of the fixedeffect model was applied in all pooled analyses in this study in consideration of the heterogeneity in study design, including patient population, ablation equipment, and power setting.
The Cochran Q test and I 2 test were performed to assess the heterogeneity of the pooled effects. Heterogeneity was considered to exist when the P value of Cochran Q test < 0:10 and I 2 > 50%. Publication biases were assessed with funnel plot, and the symmetric distribution of effect sizes was assessed visually.

Cardiovascular Therapeutics
Pooled analysis was performed with Review Manager (RevMan, Version 5.4. The Cochrane Collaboration, 2020). Jackknife Sensitivity analyses were performed for each outcome by systematically leaving out each study from pooled analyses to estimate the effect of every single study on overall estimate and track the origin of heterogeneity. Funnel, Egger's test, and meta-regression were performed with Stata (Version 14.0).
Additional subgroup analyses according to the application of antiarrhythmic drugs (AADs) postsurgery after the three-month blank period were performed because the status of AADs could be another source of heterogeneity. Since the length of blank period differed in origin studies, we set the longest blank period among included studies, 3 months, as our defined blank period. The HPSD group showed higher 12 months free from AF rate in subgroups without AADs after blank period (RR = 1:27, 95% CI: 1.08-1.49, I 2 = 0%, and P = 0:004) and with unclear AAD status (RR = 1:15, 95% CI: 1.05-1.26, I 2 = 7%, and P = 0:004). However, the free from AF rate did not show statistically significant difference between the HPSD and the conventional groups in the subgroup with unknown AAD status after the blank period (RR = 1:05, 95% CI: 0.92-1.20, I 2 = 0%, and P = 0:49). All subgroups showed low heterogeneity inside each group, and the pooled effects did not show difference among subgroups (P = 0:19) (Supplementary Figure S5a). The free from AF or AT rate 12 months postsurgery showed a similar trend. The HPSD group had higher 12 months free from AF or AT rate in subgroups without ADDs or with unclear ADD status after blank period (for subgroup without AADs, RR = 1:17, 95% CI: 1.07-1.27, I 2 = 24%, and P = 0:0004; for subgroup with unknown AAD status, RR = 1:06, 95% CI: 1.00-1.13, I 2 = 0 %, and P = 0:04). In the subgroup with continued AADs after the blank period, the difference of 12 months free from AF or AT rate between HPSD and conventional groups did not reach statistical significance (RR = 1:05, 95% CI: 0.92-1.20, I 2 = 0%, and P = 0:49). The heterogeneity inside each subgroup was low, and the pooled effects did not show difference among subgroups (P = 0:17) (Supplementary Figure S5b).  Figure 3: Forest plot of pooled effect demonstrating (a) free from atrial fibrillation (AF) for 12 months and (b) free from atrial tachyarrhythmia (AT) for 12 months in high-power short-duration (HPSD) and conventional ablation settings. 95% CI: 95% confidence interval. 10 Cardiovascular Therapeutics

Metaregression.
Both observational studies and RCTs were included in this meta-analysis. To investigate whether the type of study introduced heterogeneity into pooled effects, we performed metaregression by defining the study design as the independent variable effect size of each outcome as the dependent variable. As shown in Supplementary  Table S6, the independent variable would not significantly affect the effect size (P > 0:05 in all endpoints), indicating that it is rational to pool data from included observational studies and RCTs.

Discussion
This study is an updated meta-analysis on the efficacy, safety, and effectiveness of HPSD vs. conventional strategies in AF patients, and more importantly, the first meta-analysis made effort on distinguishing different RFA procedures of AF and focused on the classic and effective PVI procedure. We found that HPSD RFA for AF patients showed better efficacy compared with conventional group, reflected in higher first-pass PVI rate, less acute PV reconnection rate, and higher free from AF or AT rate 12 months postsurgery. This study proved a promising safety profile for HPSD setting since there was no difference between esophagus injury or other major complications between HPSD and conventional setting groups. From the aspect of effectiveness, the HPSD group showed significantly reduced total procedure time, PVI time, and PVI RF time while the rate of complete PVI did not differ between HPSD and conventional groups.
PVI has been a fundamental RFA technique for AF. However, operators may choose additional ablations on non-PV targets based on the characteristic of each patient. For instance, cavotricuspid isthmus ablation has been a well-established ablation strategy for typical atrial flutter and was typically applied to patients who have comorbidity of atrial flutter, while box isolation has become a new attempt dealing with permanent atrial fibrillation as a complement of PVI [40][41][42]. These abovementioned additional ablations reflected the heterology of each patient and introduced different extra procedure time, left atrial dwelling time, and radiofrequency time to each patient's procedure and consequent different recurrent rate of AF or AT during follow-up. Therefore, these data should not be pooled with the clear existence of the procedure heterology. Studies included additional ablations reported that HPSD groups had superior effectiveness and parallel safety profile to conventional groups which coincided with our pooled results, while the efficacy outcomes including recurrence of atrial tachycardia were disparate. Baher et al. reported that HPSD 11 Cardiovascular Therapeutics (50 W/5 s) ablation resulted in shorter procedure time, similar esophagus injury pattern, and similar long-term AF recurrence rate [43]. Bunch et al. reported HPSD group was associated with reduced procedure times, similar free from AF rate but increased rate of recurrent atrial flutter [44]. Counting the heterology and potential bias would be brought by additional ablations, and some studies though with large patients scales were excluded in this analysis if the data of additional ablations was not reported. To further evaluate the efficacy, safety, and effectiveness of HPSD-based radiofrequency ablation, more studies including rigorous design, grouping, and recording are needed.
Radiofrequency ablation, by forming permanent transmural heating lesions in left atrium tissue, blocks the ectopic current transduction to attenuate atrial fibrillation generation. During radiofrequency ablation, durable lesion formation is critical for long-term effectiveness. Power, as the parameter that impacts lesion characteristics and can be easily manipulated, has become one of the research interests to improve the quality of radiofrequency ablation. Bourier et al. demonstrated with in silico model that HPSD ablation (50 W/11 s to 13 s) had produced the equivalent lesion compared with conventional setting (30 W/30s) [9]. Another in silico model showed that higher power and shorter duration ablation settings were correlated with wider but shallower depth of lesions [45]. With an in vitro experiment, Bhaskaran et al. reported that HPSD RFA (50 W/5 s or 60 W/ 5 s) induced comparable lesion width and depth on myocardial phantom compared with standard-setting (40 W/30 s), while higher power setting (70 W/5 s and 80 W/5 s) resulted in larger lesion width [46]. Yavin et al. further proved with swine's atria that HPSD ablation (90 W/4 s) created shallower but wider lesions on ablation sites [19]. All literature mentioned above considered that higher power indeed was correlated with shallow while wide lesions with certain radiofrequency ablation settings. Therefore, HPSD setting could be a feasible and more efficient radiofrequency ablation choice in AF ablation theoretically and was supported by our pooled analysis which did not show difference in complete pulmonary vein isolation between the HPSD and conventional groups. Better efficacy outcomes were also proved by this meta-analysis; in specific, the HPSD group showed a higher first-pass PVI rate, less acute PV reconnection, and a higher rate of free from AF 12 months postprocedure. With subgroup analyses, when power ≤ 45 W or 45 W < power < 60 W, HPSD groups both showed better outcomes of 12 months free from AF or AT. Moreover, heterogeneity was minimized in the 45 W < power < 60 W subgroup in both free from AF and AT outcomes, which indicated that ablation power ≤ 45 W in the HPSD group was the source of heterogeneity. The prescription of ADDs may also introduce heterogeneity between studies so we performed subgroup analyses according to the status of ADDs application. The HPSD groups presented higher free from  76  97  97  80  45  50  41  48  61   2   2   675  14  5   595   94  51  20  100  105  45  50  35  48  47 14     160  48  60  100  107  44  28  96  220   863  761   160  48  60  100  107  90  28  96  220   188  46  60  20  107  42  28  96  174   188  47  60  20  107  90  28   13 Cardiovascular Therapeutics AF and free from AT 12-month postsurgery in subgroups both with discontinued ADDs after the blank period and subgroups with unclear ADDs status. However, in the subgroup with continued ADDs, the HPSD strategy did not show superiority over the conventional group in 12 months free from AF or AT, which may indicate that the better efficacy of the HPSD strategy can be partially complemented by ADDs. Nevertheless, selection bias brought by the different severity of AF, type of AF, etc., in origin studies may also cause this comparable result. Whether the superiority of HPSD efficacy is correlated with the shallow and wide lesion or other special characteristics, the reason HPSD creates more durable lesions requires further study. Very-highpower short duration radiofrequency ablation setting had become another attempt to improve ablation outcomes by altering the power setting recently but with limited research [8,24]. Further studies are necessary to understand the efficacy, safety, and effectiveness of higher power setting during radiofrequency ablation.
Durable lesion formation is critical for long term free from AF after radiofrequency ablation. Several integral parameters cooperating factors that matter for high-quality lesions such as FTI, ablation index (AI), lesion size index (LSI), and CLOSE protocol have been introduced into practice to improve the quality of lesions. FTI was the initial attempt to combine CF, and ablation and has been proven correlated with transmurality of RFA lesions [47]. FTI was later replaced by AI and other indexes attributed to several flaws like not counting power and the assumption of the linear relationship between CF and time. AI, a weighted nonlinear formula of contact force, power, and ablation duration, has been proven more favorable than FTI by providing more information and was able to predict PV connection [5,48]. Lesion size index (LSI), another index calculated by formula of time, power, CF, and impedance, was reported a better predictor for ablation lesion dimensions than power or CF only [3,4]. We performed subgroup analyses according to whether integral indexes or used during the procedure or not and found that either integral index-guided ablation or time-fixed ablation resulted in better free from AF or AT outcomes 12 months postsurgery. Integral indexguided ablation subgroups seemed to show a more potent outcome of free from AF than time fixed subgroup though not reached statistically significant yet. Integral indexguided ablation showed high heterogeneity while timefixed ablation did not show heterogeneity, which could attribute to pooling different index-guided ablations.
A potential advantage of HPSD radiofrequency ablation for AF is the procedure safety, especially from the prospection of esophagus thermal injury. A segment of esophagus is in direct contact with posterior wall of left atrium, and the atria portions adjacent to esophagus differed from most pulmonary vein openings to the left atrial antrum. Corresponding to the relative orientation between esophagus and left atrial, the distance from esophagus wall to endocardium range from 3.3 to 13.5 mm while the tissue thickness between pulmonary vein ostia and esophagus ranged from 7.7 to 32.8 mm [49,50]. Esophagus injury has been a spectrum of devastating complications during AF ablation. Being thinner than most parts of left atrial wall and situated nearby esophagus, ablation performed on posterior wall made the esophagus more prone to thermal injury so radiofrequency ablation has a narrow efficacy and safety window [51]. Our pooled study did not show differences in esophagus injury between HPSD and conventional groups. However, when taking the severity or classification of individual esophagus injury into account, HPSD strategy seems to show a trend of superiority. Francke et al. reported 2 of 20 (10%) and 13 of 97 (13.4%) thermal esophageal lesions in standard (conventional, 20-40 W/AI: 400-500) or HPSD (50 W/AI: 400-500) groups, respectively (P = 0:72). Both lesions in the standard group were deep ulcers and resolved slowly in 2 weeks while most lesions in the HPSD group were smaller and more superficial with only one patient developed a large ulcer [32]. Leo [28,29]. In other included studies, the power applied to posterior wall was also reduced compared with other locations in the antrum. These lowered power ablations at posterior wall could contribute to the comparative rate of esophagus thermal injury rate between HPSD and conventional groups. However, this attempt also made the safety profile of HPSD ablation at posterior wall sites remain unclear. As mentioned before, HPSD radiofrequency creates shallower lesions in silico and in vivo, which could theoretically lessen the thermal injury rate during the procedure. Whether a higher power setting is truly safe for esophagus still requires studies carefully coordinating the distance between endocardium and esophagus, the power applied during ablation, and the esophagus injury patterns in the future.
In this study, the HPSD group showed better effectiveness over the conventional group, including total procedure time, PVI time, and PVI RF time. Shortening the procedure time, especially for those patients who underwent only local anaesthesia instead general anaesthesia, helps comfort patients and therefore improves their adherence. With reduced PVI time and PVI RF time, less saline would be irrigated into circulation and may mitigate the burden of heart pump brought by overwhelmed liquid. Shorter fluoroscopic time was also reported in several studies though we did not include these data because it was hard to tell whether the fluoroscopic time was consumed by PVI or additional ablations [8,23,30]. In any case, compressing the fluoroscopic time benefits both patient and operator by reducing radiation exposure no matter the ablation type.
14 Cardiovascular Therapeutics HPSD and very high-power short-duration (vHPSD) strategies have shown satisfying efficacy, safety, and effectiveness in radiofrequency ablation treatment for AF patients in this meta-analysis. Theoretically, HPSD and vHPSD strategies can also be applied in other radiofrequency ablation treatments aiming at arrhythmia like atrial flutter, atrial tachycardia, and premature ventricular contraction. Recently, a case of successful very high-power short-duration radiofrequency ablation without periprocedural complications for frequent premature ventricular contraction with was reported [52]. Whether HPSD or vHPSD is superior to conventional radiofrequency ablation strategies requires further studies.
Although the HPSD strategy brought cardiologists a more efficient and safer way to perform transcatheter radiofrequency ablation, one should always keep in mind that AF clinical management is complex and more than ablation. Radiofrequency ablation treatment serves as rhythm control to achieve better symptom control, while anticoagulation remains the dominant therapy that lessens the thromboembolic stroke risk [53,54]. The decision of whether continue anticoagulation therapy postablation or not should be made based on stroke risk factors, e.g. CHA 2 DS 2 -VASc, instead of the AF recurrence status [54].
There were several limitations in this study. Firstly, all the studies included were nonrandomized observational studies except for only two RCTs and one randomized nonblinded study, which made the results need to be interpreted and translated cautiously. More RCTs focus on the relationship between radiofrequency power and procedure efficacy and safety should be expected and will provide more persuasive evidence. Secondary, the power settings, ablation time, contact force, AI settings, LSI settings, and the experience of individual operators differed between included studies, and the pooled analysis was not adjusted by the above variables. Although subgroup analysis is based on whether guided by AI or not and the power settings, these categorizing algorithms were still not precise enough to eliminate the heterogeneity. Thirdly, as emphasized multiple times above, the existence of additional ablation targets other than PVI impeded comprehensive analysis of the effect of power setting on AF radiofrequency treatment outcomes. Though we tried to subtract additional ablation-related procedure time or PVI time when there were detailed records and got a decent quantity of studies included for procedure parameter outcomes, the studies qualified for efficacy outcomes, i.e., free from AF and/or AT, were still limited. Future studies with more meticulous recording and analysis for each ablation target and their potential related efficacy and safety outcomes will be demanded to understand how power setting affects procedure outcomes. Last but not the least, publication bias existed in several outcomes, which may be caused by difficulties in publishing negative results. The potential publication results also require careful interpretation of corresponding results.

Conclusion
The high-power short-duration strategy showed better radiofrequency ablation procedure efficacy and effectiveness compared with the conventional ablation setting. Moreover, HPSD strategy is a safe approach with a similar complication rate for AF radiofrequency ablation procedure.

Data Availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.