Atrial fibrillation ablation compared to pacemaker therapy in patients with tachycardia–bradycardia A systematic review and updated meta-analysis

Authors: Lijun Su, Xiaoqi Wang, Fengguang Kang, Caidi Gong, Dezhu Chen

Abstract

Background:

Tachycardia–bradycardia syndrome (TBS) is a subtype of sick sinus syndrome characterized by prolonged sinus pause (≥3 s) following termination of tachyarrhythmias, primarily atrial fibrillation (AF). There is controversy regarding whether the long-term prognosis of AF ablation is superior to pacemaker implantation. This study aimed to compare the effects of AF ablation and pacemaker therapy in patients with TBS.

Methods:

We conducted a comprehensive search of electronic databases, including PubMed, Cochrane, EmBase, Web of Science, and Chinese BioMedical, up until December 1, 2023. We included studies that reported the effects of AF ablation vs pacemaker therapy in patients with TBS. From this search, we identified 5 studies comprising 843 participants with TBS who underwent catheter AF ablation or pacemaker therapy.

Results:

Our meta-analysis revealed that AF ablation and pacemaker therapy had similar effects on cardiovascular death (odds ratio [OR] = 0.62 and 95% confidence interval [CI]: 0.14–2.65), procedural complications (OR = 1.53 and 95% CI: 0.67–3.48), and cardiovascular rehospitalization (OR = 0.57 and 95% CI: 0.26–1.22). However, AF ablation provided greater benefits than pacemaker therapy in terms of all-cause mortality (OR = 0.37 and 95% CI: 0.17–0.82), thromboembolism (OR = 0.25 and 95% CI: 0.12–0.49), stroke (OR = 0.28 and 95% CI: 0.13–0.57), heart failure (OR = 0.27 and 95% CI: 0.13–0.56), freedom from AF (OR = 23.32 and 95% CI: 7.46–72.92), and prevention of progression to persistent AF (OR = 0.12 and 95% CI: 0.06–0.24). Furthermore, AF ablation resulted in a reduced need for antiarrhythmic agents (OR = 0.21 and 95% CI: 0.08–0.59).

Conclusion:

AF ablation can effectively reduce the risk of all-cause mortality, thromboembolism, stroke, heart failure, and progression to persistent AF in patients with TBS. Additionally, it may eliminate the need for further pacemaker therapy in most cases after ablation. Therefore, AF ablation is considered superior to pacemaker therapy in the management of patients with TBS.

1. Introduction

Tachycardia–bradycardia syndrome (TBS) is a subtype of sick sinus syndrome characterized by prolonged sinus pause (≥3 s) following termination of tachyarrhythmias, primarily atrial fibrillation (AF).^[1,2]^ Research has indicated that TBS patients often experience ischemic symptoms due to inadequate cardiac output resulting from the prolonged sinus pause.^[3]^ Administering antiarrhythmic drugs to treat tachycardia may exacerbate bradycardia. According to the 2018 ACC/AHA/HRS guidelines, pacemaker implantation is recommended as a class IIa treatment for TBS.^[4]^ However, complications associated with pacemakers, such as electrode dislocation and pacemaker pocket infections, may persist even after implantation. Moreover, long-term use of antiarrhythmic and anticoagulant medications in AF treatment can lead to adverse effects. Additionally, TBS patients are at increased risk of AF-related thromboembolism, heart failure, hospitalization, and progression to persistent AF.

On the other hand, recent studies have reported that catheter ablation may be more effective in maintaining sinus rhythm and reducing the need for pacemaker implantation.^[5–9]^ Therefore, guidelines suggest that catheter ablation could be considered as an alternative treatment for patients with TBS. The level of evidence supporting this recommendation is also classified as IIa.^[10]^ However, there is controversy regarding whether the long-term prognosis of AF ablation is superior to pacemaker implantation. In a previous meta-analysis, Magnano et al^[11]^ observed that AFCA in TBS patients seems to be more effective than pacemaker implantation in reducing AF recurrence and pacemaker implantation may be waived in most TBS patients treated by AFCA. Since then, several articles have been published in this field, rendering necessary an update. To summarize the existing evidence and draw credible conclusions, we conducted an updated meta-analysis of the available trials to reevaluate the optimal treatment for TBS.

2. Methods

This study adhered to the Cochrane Collaboration’s guidelines outlined in the Cochrane Handbook for Systematic Reviews and was reported in accordance with the PRISMA statement.

2.1. Search strategy and study selection

This meta-analysis was registered with PROSPERO (CRD42021292570). The systematic review and meta-analysis followed the PRISMA guidelines. A comprehensive computer-based search of PubMed, Cochrane, EmBase, Web of Science, and Chinese BioMedical databases was conducted to identify all studies published before December 1, 2023, that reported on ablation vs pacing in patients with TBS. The search strategy was (((tachycardia–bradycardia syndrome) or (tachy–brady syndrome) or (bradycardia–tachycardia syndrome)) or ((pacing) or (pacemaker)) or ((atrial fibrillation) or (atrial flutter)) or ((sinus pause) or (sick sinus syndrome))) and ((ablation) or (catheter ablation)). In addition to the computer-based search, a manual search for related articles was performed. No language restrictions were applied during the searches. The reference lists of retrieved articles were also reviewed to ensure inclusion of all eligible studies. Only studies reporting the effects of ablation vs pacing in patients with TBS were included. The exclusion criteria were as atrial fibrillation without sinus pause; treatment comparing ablation vs antiarrhythmic drugs; treatment solely with ablation; and pacing strategy involving atrioventricular junction ablation.

2.2. Data extraction and quality assessment

Two reviewers, LS and XW, independently conducted literature searches and screenings based on predetermined criteria. Data were extracted using a standardized form, which included the following information from each last name of the first author, year of publication, geographical location, sample size, placebo usage, median duration of follow-up, and cases of all-cause mortality, cardiovascular death, thromboembolism, stroke, cardiovascular rehospitalization, heart failure, freedom from AF, progression to persistent AF, usage of antiarrhythmic drugs, and procedural complications. The quality of enrolled studies was also assessed by the same investigators and the following elements were considered^[12]^: study design, characteristics of the studied population, assessment of outcome, duration of follow-up, and statistical control for potential confounding factors. Any disagreement was resolved by a discussion. All the data were extracted from published results and written informed consent for participation was not applicable. FK and CG conducted independent quality assessments of the included studies, resolving any disagreements through discussion and consensus.

2.3. Statistical analysis

The aim of the current study was to assess the prognosis of ablation and pacing in patients with TBS. The meta-analysis was conducted following the guidelines of the meta-analysis of observational studies in epidemiology group.^[13]^ The heterogeneity of the effect size among the included studies was evaluated using the I^2^-statistic and tested with a Cochrane Q test. A P < .1 was considered statistically significant.^[14]^ If no significant heterogeneity was found, the pooled effect size was estimated using the Mantel–Haenszel fixed-effects model. Otherwise, the DerSimonian–Laird random-effects model was used. The pooled analysis was conducted to examine the effects of ablation vs pacing on the prognosis of TBS. The odds ratio (OR) and its associated 95% confidence interval (CI) were reported.

To examine the stability of the pooled results, a sensitivity analysis was performed to investigate the influence of each individual study by systematically excluding them. This was done in response to potential publication bias. The study adhered to the PRISMA statement guidelines.^[15]^ Revman 5.3 was utilized to conduct all analyses and generate quality assessment graphs. STATA version 12.0 was used to carry out both the funnel plot and Egger’s test.

3. Results

3.1. Studies retrieved and characteristics

A total of 827 articles potentially relevant were retrieved through separate search strategies in each database. After reviewing the titles and abstracts, duplicate articles, irrelevant studies, case reports, and reviews were excluded. Fifty-eight studies were initially identified for further consideration. However, upon closer examination, 53 studies were subsequently excluded for the following lack of associated events data (n = 5), failure to compare ablation vs pacing (n = 8), not a cohort study (n = 28), and comparison of AF ablation vs antiarrhythmic drugs (n = 12). Hence, a total of 5 studies, involving 843 participants, met the inclusion criteria and were used in the meta-analysis.^[16–20]^ The flow diagram illustrating the process of searching and screening publications is presented in Figure 1. The characteristics of the included studies are summarized in Table 1. These studies were published between 2014 and 2023, with sample sizes ranging from 70 to 306. The median follow-up duration ranged from 1.7 to 7.7 years. The studies were conducted in China and Korea. The outcomes assessed in these studies included all-cause mortality, cardiovascular death, thromboembolism, stroke, cardiovascular rehospitalization, heart failure, freedom from AF, progression to persistent AF, usage of antiarrhythmic agents, and procedural complications. All the included studies were with unclear bias in other bias, while most studies were with high selection, performance, and detection bias and more than a half of the studies were with unclear bias in attrition and reporting bias (Fig. 2).

3.2. All outcomes of the treatment of TBS with ablation vs pacing

The incidence of all-cause mortality in patients with TBS undergoing ablation and pacing was 2.15% (8/371) and 5.47% (22/402), respectively. The results of the pooled analysis of the included studies indicated a 63% reduced risk of all-cause mortality associated with ablation (OR = 0.37, 95% CI: 0.17–0.82; Fig. 3A). The studies showed no significant heterogeneity (I^2^ = 0.0%, P > .1).

The incidence of cardiovascular death was 0.87% (2/230) in patients undergoing ablation and 1.69% (4/237) in patients undergoing pacing for TBS. The results indicated that the ablation group was not significantly associated with an increased risk of cardiovascular death (OR = 0.62, 95% CI: 0.14–2.65; Fig. 3B). No heterogeneity was found among the studies (I^2^ = 0.0%, P value > .1).

The rate of cardiovascular rehospitalization was 24.88% (101/406) among patients with TBS undergoing ablation and 40.27% (176/437) among those undergoing pacing. The results suggest that the ablation group was not significantly associated with an increased risk of cardiovascular rehospitalization (OR = 0.57, 95% CI: 0.26–1.22; Fig. 3C). The studies exhibited high heterogeneity (I^2^ = 81%, P value < .1).

Thromboembolism occurred in 2.96% (11/371) of TBS patients undergoing ablation, and 10.70% (43/402) of TBS patients undergoing pacing. The results indicated that the ablation group had a 75% reduced risk of thromboembolism (OR = 0.25, 95% CI: 0.12–0.49; Fig. 3D1). No significant heterogeneity was found among the studies (I^2^ = 0.0%, P value > .1).

The incidence of stroke in patients with TBS undergoing ablation was 3.05% (10/328), while it was 9.85% (34/345) in those undergoing pacing. The results indicated that the ablation group had a significantly lower risk of stroke, with a 72% decrease (OR = 0.28, 95% CI: 0.13–0.57; see Fig. 3D2). Furthermore, there was no heterogeneity observed among the studies (I^2^ = 0.0%, P value > .1).

The incidence of heart failure was 2.70% (10/371) in the ablation group and 8.96% (36/402) in the pacing group among patients with TBS. The results indicated that the ablation group had a 73% lower risk of heart failure compared to the pacing group (OR = 0.27, 95% CI: 0.13–0.56; Fig. 3E). No significant heterogeneity was found among the studies (I^2^ = 0.0%, P value > .1).

The event rate of procedural complications was 3.45% (14/406) and 2.29% (10/437) in patients with TBS undergoing ablation and pacing, respectively. The results suggest that the ablation group was not significantly associated with the risk of procedural complications (OR = 1.53 and 95% CI: 0.67–3.48; Fig. 3F). No heterogeneity was found among the studies (I^2^ = 21%, P value > .1).

The event rate of usage of antiarrhythmic agents was 16.44% (61/371) and 42.04% (169/402) in patients with TBS undergoing ablation and pacing, respectively. The results suggest that the ablation group was associated with a 79% decreased risk of usage of antiarrhythmic agents (OR = 0.21 and 95% CI: 0.08–0.59; Fig. 3G). There was high heterogeneity among the studies (I^2^ = 85%, P value < .1).

The event rate of being free of AF was 77.59% (315/406) and 18.99% (83/437) in patients with TBS undergoing ablation and pacing, respectively. The results suggest that the ablation group was associated with a 23-fold decreased risk of AF (OR = 23.32 and 95% CI: 7.46–72.92; Fig. 3H). There was high heterogeneity among the studies (I^2^ = 83%, P value < .1).

The event rate of progression to persistent AF was 2.16% (8/371) and 16.67% (67/402) in patients with TBS undergoing ablation and pacing, respectively. The results suggest that the ablation group was associated with an 88% decreased risk of progression to persistent AF (OR = 0.12 and 95% CI: 0.06–0.24; Fig. 3I). No heterogeneity was found among the studies (I^2^ = 0.0%, P value > .1).

3.3. Sensitivity and publication bias

We observed significant heterogeneity in the results of cardiovascular rehospitalization, usage of antiarrhythmic agents, and freedom from AF. Therefore, we conducted a sensitivity analysis to assess the stability of the pooled results. Exclusion of the study conducted by Zhang et al resulted in no significant heterogeneity (I^2^ = 0%, P value = .98) in the cardiovascular rehospitalization outcome. This suggests that the heterogeneity observed in this outcome was primarily influenced by this particular study. Similarly, exclusion of the study conducted by Cho et al^[18]^ resulted in mild heterogeneity (I^2^ = 44%, P value = .17) in the usage of antiarrhythmic agents outcome, indicating that this study was the source of heterogeneity for this outcome. In the case of freedom from AF outcome, exclusion of the study conducted by Cho et al^[18]^ revealed moderate heterogeneity (I^2^ = 60%, P value = .06), suggesting that this study contributed to the observed heterogeneity. According to Begg’s test for publication bias, there is some evidence of bias (Kendall’s score = 4, P = .18, Fig. 4).

4. Discussion

The present meta-analysis involved 5 studies^[16–20]^ encompassing approximately 843 individuals, and revealed 4 significant findings. First, catheter ablation was found to lower the risk of stroke, and heart failure in comparison to pacemaker implantation. Second, patients who underwent AF ablation exhibited better maintenance of sinus rhythm and a reduced risk of progression to persistent AF, resulting in a significant decrease in the need for antiarrhythmic drugs. Third, there were no noteworthy differences in cardiovascular death and rehospitalization between AF ablation and pacemaker implantation. The aforementioned situation is largely in line with findings from previous meta-analyses.^[11]^ Fourth, catheter ablation was shown to reduce the risk of all-cause mortality and thromboembolism compared to pacemaker implantation. There was no significant difference in procedural complications between AF ablation and pacemaker implantation. These findings differ from those of previous meta-analyses.^[11]^ Sinus node dysfunction (SND) encompasses several arrhythmias that disrupt the normal pacing function of the heart, such as sinus bradycardia, sinus arrest, sinoatrial block, and alternating episodes of tachycardia (TBS). TBS, a specific subtype of SND, often occurs due to the termination of atrial fibrillation, atrial flutter, or atrial tachycardia. However, it is important to note that the patient may not necessarily have significant dysfunction of the sinus node. Currently, there are multiple theories to explain TBS, including overdrive inhibition of sinus node pacing function by tachycardia, increased vagal tension, fatty infiltration, and extensive fibrosis of the sinus node or surrounding junctional regions. While antiarrhythmic agents can be used to treat atrial fibrillation, their use in TBS patients is limited because they can increase the risk of sinus arrest following the termination of atrial fibrillation. Therefore, permanent pacemakers are typically implanted, or catheter ablation is used to treat atrial fibrillation. However, due to concerns regarding the prolonged sinus pause, many physicians prefer pacemaker implantation.

For the long-term treatment of TBS, it is important to maintain sinus rhythm and control ventricular rate. Our study found that the ablation group had a 79% lower use of antiarrhythmic drugs compared to the pacing group (OR = 0.21 and 95% CI: 0.08–0.59). Although the pacemaker group used more antiarrhythmic drugs to maintain sinus rhythm, AF ablation was associated with a 23-fold reduction in the risk of AF compared to the pacing group (OR = 23.32 and 95% CI: 7.46–72.92). This indicates that ablation has a superior effect in maintaining sinus rhythm compared to antiarrhythmic drugs, which is consistent with previous findings.^[8]^ Conversely, several studies have reported a significant proportion of patients developing persistent atrial fibrillation after pacemaker implantation during long-term follow-up.^[21–23]^ Our study suggests that the ablation group had an 88% lower risk of progression to persistent AF (OR = 0.12 and 95% CI: 0.06–0.24). These results align with previous studies. Therefore, ablation can more effectively maintain sinus rhythm and reduce the need for antiarrhythmic drugs, ultimately decreasing the arrhythmogenic effect. Additionally, it can alleviate the burden of AF, thus reducing the occurrence of thromboembolism.

Thromboembolic events, heart failure, all-cause mortality, and cardiovascular hospitalization are important outcomes for evaluating the long-term prognosis of patients with thrombosis (TBS). Kristensen et al demonstrated that atrial fibrillation is an independent risk factor for thrombotic events in patients who have undergone pacemaker implantation (RR: 7.5, 95% CI: 1.6–36.2, P = .01).^[24]^ In our study, we discovered that the ablation group had a 74% lower risk of thromboembolism (OR = 0.25 and 95% CI: 0.12–0.49). Anticoagulation is a crucial treatment for AF. Given that most patients who undergo pacemaker implantation are elderly and suffer from multiple comorbidities, some physicians have concerns about the potential for fatal bleeding. Additionally, poor long-term compliance with anticoagulation poses a challenge. Currently, the rate of anticoagulation for AF remains unsatisfactory in China.^[25]^ The inadequate long-term compliance with anticoagulation contributes to an increased risk of embolism. Our study demonstrated that despite anticoagulant therapy, embolic events were still significantly higher in the pacemaker implantation group compared to the ablation group. Moreover, previous studies have indicated that maintaining sinus rhythm after catheter ablation can reduce the risk of stroke more effectively than drug therapy alone.^[26]^ But however, even after undergoing AF ablation, patients may still need to continue anticoagulation therapy, based on their CHA2DS2-VASc score.

Our study found that the ablation group had a 71% lower risk of heart failure compared to the pacing group (OR = 0.27, 95% CI: 0.13–0.56). This can be attributed to several radiofrequency ablation is effective in maintaining sinus rhythm, which helps restore left atrial pump function and reduces pressure on the left atrium and pulmonary veins. This, in turn, reduces the incidence of heart failure; maintaining sinus rhythm also decreases the likelihood of tachycardia cardiomyopathy caused by AF; by reducing the adverse effects of antiarrhythmic drugs on myocardial strength, ablation can prevent the onset of heart failure; pacing may lead to pacing-induced cardiomyopathy.

Although ablation was not significantly associated with the risk of cardiovascular death and rehospitalization, it was associated with a 62% decreased risk of all-cause mortality (OR = 0.37, 95% CI: 0.17–0.82). This decrease can be attributed to the reduction in the risk of thromboembolism, heart failure, and the use of antiarrhythmic drugs.

There were no significant differences in procedural complications between these 2 groups. Chen et al^[16]^ identified femoral hematoma and deep vein TBS as complications of the ablation procedure. Cho et al^[18]^ reported procedure-related cardiac tamponade as a complication of the ablation procedure, while the infection was identified as a complication of the pacing procedure. However, complications from other relevant studies were not addressed.

Only a small percentage of TBS patients require pacemaker implantation due to cardiac arrest following ablation. According to a previous study, pauses lasting 6.3 seconds or longer after AF termination were significantly associated with the need for permanent pacemaker implantation after ablation (HR = 1.332, 95% CI = 1.115–1.591; P = .002).^[27]^ The results indicate that ablation can restore sinus node function when sinus arrest is caused by sinus node overdrive inhibition due to tachyarrhythmia. However, patients with severe SND may require pacemaker implantation after ablation. Therefore, the decision to perform ablation or pacemaker implantation should be based on the individual patient’s circumstances for TBS patients. Ablation can be considered the primary treatment option for young patients with few comorbidities who present with palpitations. Pacemaker implantation may be the preferred option for elderly patients with multiple comorbidities who present with syncope. Additionally, close follow-up is recommended for patients after ablation. Long-term wearable electrocardiographic monitoring equipment is preferable for detecting prolonged intermittent sinus arrest. Alternatively, esophageal pacing examination can be used to assess the recovery of sinus node function.

Some limitations of the current study should be noted. First, prior studies have not elucidated the recovery of sinus function following successful radiofrequency ablation to restore sinus rhythm, necessitating further investigation through in-depth electrophysiological experiments. Second, the patients included in the aforementioned studies utilized traditional right ventricular pacing, which inherently poses deleterious effects on cardiac function. Persistent use of right ventricular apical pacing escalates the risk of atrial fibrillation, rehospitalization for heart failure, and pacing-related cardiomyopathy, among other complications. Recently, His-bundle pacing and left bundle branch area pacing which involves direct stimulation of the His-Purkinje conduction bundle, has emerged as a potential solution to synchronize ventricular activation and restore physiological pacing pathway. This technique demonstrates a significant reduction in incidences of heart failure and mortality,^[28]^ thereby potentially establishing a novel treatment option for TBS patients in the future. Third, all the studies considered solely encompassed the Asian population, thus raising uncertainty about the generalizability of these findings to other ethnic groups. Fourth, gender serves as one of the factors indicating the need for anticoagulation in AF. Okumus et al^[29]^ exposed a higher likelihood of pacemaker implantation among women compared to AF ablation. However, since the studies lack gender-specific data, it is impossible to acquire comparative outcomes in pacemaker implantation and ablation based on gender. Finally, the majority of studies were retrospective, thus introducing the potential for publication bias. The included studies were not randomized trials, although the results are promising, confirmation would require a randomized trial.

5. Conclusion

In patients with TBS, catheter ablation has shown a potential to decrease the risk of all-cause mortality, thromboembolism, stroke, heart failure, and progression to persistent AF. In many cases following catheter ablation, it has been observed that the need for additional pacemaker implantation can be avoided. RF ablation appears to be a more effective treatment compared to pacing in patients with TBS. Additional research is necessary to validate the current findings.

Author contributions

**Writing—original ** Lijun Su, Xiaoqi Wang.

**Formal ** Fengguang Kang.

Methodology: Fengguang Kang.

Investigation: Caidi Gong.

**Writing—review & ** Dezhu Chen.