New Pacemaker Implantation in Patients undergoing Transcatheter Valve Replacement: a systematic review and meta-analysis

Background Permanent pacemaker (PPM) implantation remain a common nding after Transcatheter aortic valve replacement (TAVR). Overall rate of PPM implantation after TAVR varies and is related to various factors and is highly variable. The purpose of this review is to evaluate the incidence of new permanent pacemaker implant at 1 year irrespective of valve brand manufacturer, vascular access used, deployment technique/mechanism. Secondary outcomes included all-cause mortality, 30-day, 1-year mortality, and cardiovascular mortality. Methods We performed a systematic search for studies that reported the incidence of PPM implantation after TAVR. Data on study, patient, and procedural characteristics were abstracted. Risk ratios (RRs); odds ratio (OR) and 95% condence intervals were calculated by use of random effects models. Results 14 studies were included, totalling 25,967 TAVR patients, mean age 80.15 ± 6.91years, 52.9% being male, 26.3% of which required PPM implantation 1-year after intervention (p = 0.00001; RR 115.16). Conclusions Various factors impact the risk for pacemaker implantation after TAVR and one quoter of the patients undergo new permanent pacemaker implant at 1-year post undergoing TAVR.


Introduction
Aortic valve replacement (AVR) is the mainstay of treatment of symptomatic severe aortic stenosis (AS). Transcatheter aortic valve implantation (TAVI; or transcatheter aortic valve replacement [TAVR]) is now more a safe and feasible alternative to surgical aortic valve replacement (SAVR), especially in high surgical risk patients. 1,2 Among procedural complications including arrhythmias (eg, conduction abnormalities and atrial brillation) may arise. Risk factors such as atrioventricular block, pre-existing right bundle branch block, new left bundle branch block and use of a CoreValve (versus SAPIEN valve) have been associated need for new permanent pacemaker (PPM) implantation. 3,4 Post-TAVR overall new PPM implantation rate varies and is related to pre-procedural and intraprocedural factors. Some studies reported rates of new PPM or intracardiac de brillator implant of about 8-17 percent. [5][6][7] Other studies report incidence as high as 21-42.5 percent. 8,9 Current data regarding the impact of TAVR on conduction system, new PPM requirement on mortality is still con icting.
In this meta-analysis we tend to evaluate the incidence of new permanent pacemaker implant at 1 year irrespective of valve brand manufacturer, vascular access used, deployment technique/mechanism (auto-expandable vs mechanical). Secondary outcomes included all-cause mortality, 30-day, 1-year mortality, and cardiovascular mortality.

Overview
We did a systematic review and meta-analysis of studies on prevalence and outcomes of arrhythmic mitral annular disjunction. The review is reported according to PRISMA guidelines.
Search strategy, selection criteria, and data extraction Quality appraisal The quality appraisal was established according to Le Floch and colleagues' criteria, by two independent assessors (HF and HM). 24 This tool appraises the quality of the study based on the following questions: Did this article give an answer to the research question? Did the article focus clearly on the research question? Was the methodology appropriate? Do you believe the results? (Can it be due to chance, bias or confounding?). To be included, the article had to score "yes" on every question.

Statistical analysis
Quantitative meta-analysis was done for an outcome when more than one study presented relevant data. We excluded individual outcomes from studies reporting no adverse outcomes in one or both groups, and studies not satisfying the normality assumption for continuous variables.
A random-effects estimate of the pooled odds of each outcome was generated with use of the Mantel-Haenszel method. Between-study heterogeneity was explored using the I 2 statistic, with substantial heterogeneity de ned as an I 2 value greater than 50%. We reported p values and the amount of accounted heterogeneity for each covariate. Potential publication bias was assessed with Egger's test and funnel plots for visual inspection when su cient studies (n>10) were available. Statistical analyses were performed using the Revman software package (Review Manager, Version 5.4. Copenhagen, The Nordic Cochrane Centre, the Cochrane Collaboration).

Results
Characterization of the study population: Twenty-ve thousand nine hundred and sixty-seven patients totalled from the fourteen studies included. The characteristics of the patients are shown in Table 1. The average age was 80.15 ± 6.91years, 52.9% being male.
The prevalence of reported hypertension and coronary artery disease was high 76.6% and 59.7%, respectively; diabetes was reported in 30.2%. Of the studies that reposted the prevalence of heart failure was 49.3%. Pre-procedural risk was assessed by the logistic EuroSCORE or the STS-PROM score in the majority of included studies, although in 5 studies, did not report on the risk score.

Discussion
Post-TAVR conduction disturbances such as new onset left bundle brunch block (LBBB) are still the one of the main setbacks of the procedure. It may occur within the rst 24 hours post-procedure, even though most events acutely during valve expansion, new-onset LBBB may occur before valve implantation, during guidewire insertion and balloon predilation. 25,26 The results of the present studies showed that about one quarter (26.3%) implanted permanent pacemaker (PPM) at 1-year. Previous studies report a 1-year implant rate between 5-20%. 27,28 Recent published data from the MARE study reports an annual rate of PPM implantation of 7.3%. 29 New LBBB may occur beyond 6 months and at 1-year in about 57% of the patients, and in up to 2.9% of patients beyond 1-year. 30,31 In this study we did not assess the clinical predictors of as it was not in our scope and there have been reported by other studies. Diabetes mellitus, previous coronary artery bypass graft, female sex, the amount of calci cation of the aortic valve, and pre-existing conduction abnormalities (e.g. prolonged QRS duration) have been identi ed as risk factors new onset LBBB. 32,33,34 In the present analysis we taught to investigate the incidence of post-TAVR PPM implant, irrespective of valve brand, deployment mechanism and/or vascular access because previous studies reports on incidence are highly variable. Previous studies assessing the rate of PPM post-TAVR using rst generation valves range from 2-51%. 35 There have been some contradictory data regarding mortality in patients with TAVR and new PPM, suggesting a possible correlation and increased mortality. 36,37 In our meta-analysis we did not assess the correlation between PPM on mortality as we did not have access to individual patient data and subgroups. As so, we evaluated overall mortality rates. However, a meta-analysis showed that PPI post-TAVR was not associated with any increased risk of all-cause mortality at 1 year (RR, 1.03; 95% CI, 0.9-1.18), furthermore there was a trend towards a protective effect on cardiac death was observed (RR, 0.78; 95% CI, 0.60-1.03). 38

Study Limitations
The current study had following limitations: 1) there were several clinical variables, but we did not aim to systematically examine them. 2) Follow-up data as well as clinical outcomes related to PPM were not reported in most of the studies. Thus, we could not address the clinical long-term effectiveness of PPM implantation in these patients. 3) A clear indication/diagnosis leading to pacemaker implantation was not possible assess in most of the studies.

Conclusions
Various factors impact the risk for pacemaker implantation after TAVR and although there's Still con icting data regarding the incidence, this study showed that at least one quoter of the patients undergo new permanent pacemaker implant at 1-year post undergoing TAVR. Adverse effects of new pacemaker on morbidity and mortality after TAVR, as well as long term mortality must be evaluated in by further research to improve risk-strati cation and better identify predictors of poor outcome.

Declarations
Authors contributions: Study design/data analysis (HF), re-checking of data collected (HM/ARF), Drafting article (HF), Critical revision of article article approval of article (FM/CM).   Figure 1 Primary Outcome

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