Clinical Impact of Preexisting Right Bundle Branch Block after Transcatheter Aortic Valve Replacement: A Systematic Review and Meta-Analysis

Introduction Transcatheter aortic valve replacement (TAVR) is now the treatment of choice for patients with severe aortic stenosis regardless of their surgical risk. Right bundle branch block (RBBB) can be a predictor for development of significant atrioventricular (AV) block after TAVR, requiring permanent pacemaker implantation (PPI). However, data related to the risk of PPI requirement with preexisting RBBB is scarce. Hence, this systematic review and meta-analysis aims to assess clinical outcomes of patients undergoing TAVR with RBBB on preexisting electrocardiogram. Methods We performed a systematic literature review to identify randomized and nonrandomized clinical studies that reported any clinical impact of patients undergoing TAVR with preexisting RBBB. A total of eight databases including PubMed (Medline), Embase, Cochrane Library, ACP Journal Club, Scopus, DARE, and Ovid containing articles from January 2000 to May 2020 were analyzed. Results We identified and screened 224 potential eligible publications through the databases and found 14 relevant clinical trials for a total of 15,319 participants. There was an increased 30-day pacemaker implantation rate of 38.1% in the RBBB group compared to 11.4% in the no RBBB group with a risk ratio of 3.56 (RR 3.56 (95% CI 3.21–3.93, p < 0.01)). There was an increased 30-day all-cause mortality in the RBBB group of 9.5% compared with 6.3% in the no RBBB group with an odds ratio of 1.60 (OR 1.60 (95% CI 1.14–2.25, p < 0.01)). Conclusion This study indicates that patients with preexisting RBBB have higher incidence of PPI and all-cause mortality after TAVR compared with patients without RBBB. Further trials are needed to compare the clinical outcomes based on TAVR valve types and assess the benefit of PPI in patients with new-onset RBBB after TAVR.


Introduction
Transcatheter aortic valve replacement (TAVR) has revolutionized the current era of modern medicine by becoming the treatment of choice for patients with symptomatic severe aortic stenosis regardless of their surgical risk [1]. However, the high frequency of conduction disturbances, such as left bundle branch block (LBBB) and atrioventricular block, and the subsequent need for permanent pacemaker implantation (PPI) remain a challenge [2,3]. Preexisting right bundle branch block (RBBB) has been established as a risk factor for PPI after TAVR [4,5]. Preexisting RBBB in the general population and in patients with heart disease has been associated with increased risk of mortality [6]. However, data on the prognostic impact of preexisting RBBB on clinical outcomes after TAVR is limited. is systematic review and meta-analysis evaluates the impact of preexisting RBBB on clinical outcomes in patients undergoing TAVR.
contains a checklist of 27 items required of systematic reviews and meta-analyses. e review was not registered a priori. No ethical approval was required since this metaanalysis uses only public published data.

Search Strategy.
We performed a systematic literature review to identify randomized and nonrandomized clinical studies that reported any clinical impact of patients undergoing TAVR with preexisting RBBB. Searches were limited to peer-reviewed primary research articles published in English, French, and Spanish up to May 17 th , 2020. is research involved human subjects and described the clinical impact of RBBB on patients who underwent TAVR. We developed the search strategy according to available guidance from the Cochrane Collaboration. e search strategy in MEDLINE explored Medical Subject Heading (MeSH) terms related to patients with TAVR and history of preexisting RBBB. e following search strategy was applied to search MEDLINE and we adapted it for the other databases: ("transcatheter aortic valve replacement"[MeSH Terms] OR ("transcatheter"[All Fields] AND "aortic"[All Fields] AND "valve"[All Fields] AND "replacement"[All Fields] AND "implantation"[All Fields])) OR "transcatheter aortic valve replacement"[All Fields]) AND ("bundle-branch block"[MeSH Terms] OR ("bundle-branch"[All Fields] AND "block"[All Fields]) OR "bundle-branch block"[All Fields] OR ("right"[All Fields] AND "bundle"[All Fields] AND "branch"[All Fields] AND "block"[All Fields]) OR "right bundle branch block"[All Fields]). e articles found to be relevant during the hand search were stored in EndNote. Selected articles underwent full evaluation to assess their potential inclusion in the systematic review.

Study Selection.
Articles were selected for inclusion based on predefined criteria, which included age, sex, TAVR, and preexisting RBBB, and the primary or secondary outcomes being mortality and clinical outcomes. Exclusion criteria were patients with LBBB and patients with normal sinus rhythm. We excluded case reports and studies with fewer than 10 subjects.
Two authors (GS, SL) independently read the trials and screened the abstracts to choose potentially relevant articles. Risk of bias in the studies was assessed at an individual level of each study. Selected articles underwent full evaluation to assess their potential inclusion in the systematic review.

Statistical Analysis.
Data were analyzed using Review Manager Software 5.3. We used fixed effects to assess the combined risk estimates according to I2 statistics. Analysis to determine sensitivity and publication bias was detected by funnel plots. p < 0.05 was considered statistically significant.

Literature Search.
Our search yielded 224 abstracts. We excluded 199 studies at the abstract level and selected 24 full-text articles for detailed assessment; 14 studies were ultimately included in our systematic review and 11 studies were included in our meta-analysis. Figure 1 describes the flowchart of included studies. Table 1 shows the baseline characteristics of the included studies. All studies were published between 2010 and 2020. e 14 studies included 15,319 patients with 1,654 cases of preexisting RBBB. In nine of the included studies, preexisting RBBB was retrospectively identified as a risk factor for PPI. erefore, baseline characteristics for patients with preexisting RBBB were not reported in these nine studies. For studies that did report characteristics for both RBBB and non-RBBB patients, the median age of the participants was 82.0 IQR (81. 4-84.0 [10]. Tovia-Brodie et al. did not report a 30-day PPI rate as they compared whether prophylactic PPI improved outcomes in patients with preexisting RBBB [11]. e nine remaining studies identified risk factors for 30day PPI as summarized in Table 2 [14]. Guetta el al. identified preexisting RBBB and deep valve implantation as risk factors for PPI after TAVR in their retrospective review at three referral centers in Israel [20].

Baseline Characteristics of the Studies.
Meta-analysis of the included studies revealed a higher 30-day PPI rate of 38.1% in patients with preexisting RBBB when compared to a 30-day PPI rate of 11.4% in patients with no RBBB. is is a statistically significant increase in 30-day PPI rate in patients with preexisting RBBB with a risk ratio of 3.56 (95% CI 3.21-3.93, p < 0.01). e forest plot for 30-day PPI rate is shown in Figure 2. Husser et al., Tovia-Brodie et al., and van Gils et al. results were not included in the 30-day PPI meta-analysis as these studies only included patients with preexisting RBBB and made no comparisons to patients without RBBB. In the two included studies that reported 30-day mortality as an outcome, meta-analysis revealed a higher 30-day mortality rate of 9.5% in patients with preexisting RBBB compared to a 30-day mortality rate of 6.3% in patients with no RBBB.
is is a statistically significant increase in 30-day mortality in patients with preexisting RBBB with a risk ratio of 1.60 (95% CI 1.14-2.25, p < 0.01). e forest plot for 30-day morality rate is shown in Figure 3.

Discussion
is is the first systematic review and meta-analysis to demonstrate the impact of preexisting RBBB on new pacemaker implantation after TAVR. Our findings are derived from 14 studies reporting clinical outcomes in a total of 1,654 patients with preexisting RBBB after TAVR. e Full-text articles excluded (n = 10) Editorial/review (4) 30-day PPI not reported (5) Compared approach for new-onset BBB (1) Studies included in qualitative synthesis (n = 14) Studies included in quantitative synthesis (meta-analysis) (n = 11)   [21][22][23][24][25][26][27][28]. Bussink et al. found RBBB to be associated with increased all-cause and cardiovascular mortality in both men and women from the general population [21]. Abdel-Qadir et al. found no prognostic value of RBBB in patients hospitalized with heart failure; however, Barshehet et al. found RBBB to be associated with increased long-term mortality risk in hospitalized patients with systolic heart failure [22,23]. Melgaregjo-Moreno et al. found new permanent RBBB to be associated with increased 30-day and seven-year mortality in patients with acute myocardial infarction [24]. Wong et al. found RBBB accompanying anterior acute myocardial infarction to be associated with increased 30-day mortality [28]. Long-term epidemiological studies in men from the general population have found a higher incidence of RBBB with aging, hypertension, and diabetes mellitus [25,26]. Zhang et al. found RBBB in women with cardiovascular disease to be associated with an increased risk of coronary heart disease death over 14 years of follow-up. However, RBBB in women free of cardiovascular disease was not associated with increased mortality [27]. Meta-analysis completed by Xiong et al. found RBBB to be associated with an increased risk of mortality in the general population and in patients with heart disease [6]. e exact mechanism by which RBBB increases mortality has not been elucidated, although underlying conduction system disease can predispose patients to various arrhythmias. e association of RBBB with decreased left ventricular ejection fraction in patients with prior myocardial infarction or heart failure may provide a clue towards the underlying mechanism [23,28]. e various comorbidities and underlying heart disease in patients with RBBB may also explain the increased mortality.
A previous meta-analysis by Siontis et al. demonstrated the significance of RBBB in the requirement for PPI after TAVR. Male sex, first-degree AV block, left anterior hemiblock, and intraprocedural AV block were also found to be predictive of PPI after TAVR [4]. e newer studies highlighted in this meta-analysis emerged to specifically focus on the clinical impact of preexisting RBBB after TAVR, which is important for improving patient outcomes [7][8][9][10]. Journal of Interventional Cardiology 5 In TAVR, conduction disturbances are a common complication likely due to direct insult to the left bundle branch because of the anatomical relationship between the aortic annulus and the conduction system [29]. New-onset LBBB develops in 5% to 65% of patients undergoing TAVR, and its persistence can result in PPI in 15% to 20% of cases [29]. New-onset LBBB after TAVR has been associated with increased risk of cardiac death and PPI at one year follow-up [30]. Preexisting RBBB with new-onset LBBB after TAVR will usually generate PPI during the index hospitalization. Chorianopoulos et al. demonstrated that postprocedural bradyarrhythmias develop in 36.2% of patients after TAVR with 3.8% remaining >96 hours after TAVR. Preexisting RBBB was found to be the only predictor of postprocedural bradyarrhythmias [5]. Late-onset new LBBB >3 months after TAVR is a rare complication seen in only 0.8% of patients [31]. Development of high degree AV block is a common complication seen in up to 58.8% of patients with preexisting BBB or BBB occurring during TAVR [32]. ese late conduction disorders in patients with preexisting RBBB can lead to cardiac complications such as heart failure and sudden cardiac death.
is systematic review and meta-analysis reveals increased PPI, all-cause mortality, and cardiac mortality in patients with preexisting RBBB after TAVR. is is clinically significant given the recent trend towards early discharge after TAVR [33]. Patients with preexisting RBBB may need additional monitoring after TAVR to detect conduction disturbances and ensure safe discharge. Early electrocardiographic monitoring may be beneficial as part of the TAVR work-up as Urena et al. found that newly diagnosed preprocedural arrhythmias are common and associated with higher rates of PPI after the procedure [34]. Additional strategies for managing preexisting RBBB in patients undergoing TAVR may emerge as we understand more about conduction disturbances following TAVR.
Preexisting RBBB is a common underlying conduction disturbance in patients undergoing TAVR and is associated with increased risk of PPI at 30 days and all-cause and cardiovascular mortality. Future studies will be needed to evaluate optimal management of patients with preexisting RBBB undergoing TAVR. Larger prospective studies are needed to investigate the optimal timing for PPI after TAVR and to evaluate prophylactic PPI in patients with preexisting RBBB prior to TAVR. Larger prospective studies are needed to investigate strategies for early detection of conduction disturbances in patients with preexisting RBBB. Until more data is available, there are many multicenter and literaturebased decisional algorithms to guide PPI decision-making [35]. Careful monitoring to detect arrhythmias after TAVR may be necessary to improve clinical outcomes in patients with preexisting RBBB.  Journal of Interventional Cardiology lead to confounders influencing the relationship between preexisting RBBB and outcomes [7]. e studies by Husser et al. and van Gils et al. are limited by their observational design [8,9]. Tovia-Brodie et al. used a single-center retrospective design and did not use randomization to determine prophylactic pacemaker implantation [11]. e results from Watanabe et al. are limited by the relatively small size of the cohort (n � 749) and the relatively short median follow-up of 16 months [10]. e retrospective studies of existing data are subject to all of the limitations inherent to this study design [12][13][14][15][16][17][18][19][20]. Availability of specific data points, such as medication that could influence cardiac conduction, is a common limitation for retrospective studies. Roten [16][17][18][19][20]. All of the included studies are likely influenced by between-center variability and the lack of centralized independent assessment of procedural results and outcomes. e various valve types used in each study likely influence the generalizability of the aggregate data as specific valve types have shown different rates of procedural complications.

Conclusion
Conduction issues after TAVR continue to remain a common complication during the management of severe aortic stenosis. is current systematic review and meta-analysis indicates that patients with preexisting RBBB have a higher incidence of PPI and all-cause mortality after 30 days after TAVR compared with patients without RBBB. Further trials are needed to compare the clinical outcomes based on TAVR valve types and assess the benefit of PPI in patients with RBBB after TAVR. In addition, understanding the progression and prevention of electrical conduction disease are necessary for appropriate risk stratification, interventional strategy, and avoidance of pacemaker implantation.

Data Availability
e data used to support the findings of this study are included within the article.

Conflicts of Interest
e authors declare no conflicts of interest.