Comparing outcomes of balloon-expandable vs. self-expandable valves in transcatheter aortic valve replacement: a systematic review and meta-analysis

Background: Aortic stenosis (AS) is a common heart condition categorized into congenital and acquired forms. Transcatheter aortic valve replacement (TAVR) is an innovative method for AS management, and two valve types, self-expanding valves (SEV) and balloon-expandable valves (BEV), are used in TAVR. The objective of this study is to compare the clinical outcomes associated with balloon-expandable and self-expandable valves in transcatheter aortic valve replacement. Methods: The researchers conducted a comprehensive meta-analysis following PRISMA guidelines and AMSTAR-2 tool. The methodology involved a systematic literature search, strict eligibility criteria, unbiased study selection, meticulous data extraction, quality assessment, and rigorous statistical analysis. Results: Our analysis included twenty-six papers and 26 553 patients. BEV exhibited significant advantages over SEV in overall mortality across 21 studies, particularly in perioperative and 30-day assessments. However, no substantial disparities emerged between the two valve types in stroke incidence. BEV demonstrated notable benefits in reducing hospitalization rates across 6 studies and significantly fewer instances of permanent pacemaker implantations across 19 studies, particularly evident in the perioperative setting. Other secondary outcomes like bleeding, acute kidney injury, and myocardial infarction showcased non-significant differences between BEV and SEV. Conclusion: The analysis indicates that BEV may offer benefits in specific aspects of TAVR outcomes, but further research is needed to fully understand the factors influencing patient outcomes and mortality in TAVR procedures.


Introduction
Regarded as the most common cause of left ventricular outflow obstruction, aortic stenosis (AS) affects at least 5% of the population, with incidence rates increasing with age [1] .From an aetiological perspective, AS is categorized into two typescongenital AS, where an individual has the disorder since birth, and acquired AS.In developing nations, rheumatic fever remains the leading cause of acquired aortic stenosis-the clinical manifestations of the disease range from dyspnoea on exertion to chest pain and fatigue.However, in some severe cases, AS can cause heart failure [2] .
Echocardiography remains the imaging modality for diagnosing aortic stenosis, with aortic valve replacement (AVR) being the treatment choice and is considered superior to medical management.Transcatheter aortic valve replacement (TAVR) has emerged as an innovative transformation in AVR surgeries, offering a less invasive alternative to traditional surgical valve

HIGHLIGHTS
• In this systematic review, we have compared the outcomes of balloon-expandable vs. self-expandable valves in transcatheter aortic valve replacement.• Our findings suggest potential advantages of balloonexpandable valves in terms of mortality and fewer hospitalizations.• Further research is still warranted to evaluate the two options, particularly considering the non-significant results for cost-effectiveness and patient-reported outcomes.
replacement [3] .Over the last few decades, TAVR has witnessed a steep rise, revolutionizing the landscape of cardiovascular interventions.The fact that TAVR can deliver remarkable patient benefits, including reduced blood loss, fewer complications, and shorter hospital stays, among others, contributes to this.This minimally invasive procedure involves the insertion of a collapsible valve via a catheter, usually through the femoral artery or alternative access routes, negating the need for open-heart surgery.The valve is positioned within the native aortic valve annulus and then expanded or self-expanded (depending on the type) to replace the dysfunctional valve, thus restoring proper blood flow and alleviating symptoms.While there are currently multiple options in the TAVR market, only two are approved by the Food and Drug Administration (FDA).They are CORE valves (Medtronic Fridley) and SAPIEN valves (Edwards Lifesciences) [3] .SAPIEN valves consist of bovine pericardial tissue and chromium cobalt alloy.SAPIEN valves can be balloon expanded.The EVOLUT-R is the newest generation Medtronic valve.It's made of pig tissue with a nitinol frame.This valve is self-expandable (it does not require balloon inflation) and repositionable after deployment.
While multiple studies have provided valuable insights, they have often overlooked the broader picture.This comprehensive meta-analysis presents another perspective by combining and subgrouping outcomes within specific time frames.Through this study, we aim to contribute to the knowledge surrounding TAVR, offering a comprehensive assessment of the comparative advantages of self-expanding valves (SEV) and balloon-expandable valves (BEV).In doing so, we provide clinicians and researchers with valuable insights to inform their decision-making processes and optimize patient care in the dynamic field of transcatheter aortic valve replacement.

Materials and methods
The researchers conducted this meta-analysis following the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines [4] .The work has been reported in line with the AMSTAR (Assessing the methodological quality of systematic review) tool.

Eligibility criteria
The eligibility criteria followed the PICOS strategy: Population: Patients undergoing TAVR via SEV or BEV.Intervention: BEV.Comparators: SEV.Study design: Randomized controlled trials (RCT) and observational studies comparing the techniques.
Outcome: Studies that reported our outcomes of interest were included.These outcomes were: Primary outcomes: Mortality, Stroke and Hospitalization Secondary outcomes: Permanent pacemaker, bleeding, acute kidney injury, and myocardial infarction.

Study selection and data extraction
All studies were screened for inclusion using the eligibility criteria detailed above.The selected articles were subsequently analyzed in their entirety by two of the investigators.This data were extracted into a pre-structured Microsoft Excel data sheet (Version 2019, Microsoft).Disagreements were resolved by consulting a separate author.The following data were extracted from the studies: First Author, the year of publication, country of origin, study design, age, gender, BMI (kg/m 2 ), and outcomes of interest.

Quality assessment
The relevant studies were assessed for quality via the Cochrane risk-of-bias (RoB2) tool [5] for RCTs and the Newcastle-Ottawa Scale (NOS) for observational studies [6] .Two independent reviewers performed the quality assessment, and any discrepancy was resolved by consultation with another author.

Statistical analysis
Data analysis was performed using the comprehensive metaanalysis (CMA) version 3.0.We presented dichotomous data as odds ratios (ORs) and continuous data as mean differences (MDs).A random-effects model was used to deal with the heterogeneity of included studies.An I2 index greater than 75 is

Study characteristics
The characteristics of the included studies are shown in Table 1.There were 26 553 patients in the BEV group and 14 953 in the SEV group; hence, a total of 41 506 patients are included in this meta-analysis.

Risk-of-bias assessment
According to the RoB2 tool, six of the seven RCTs explained the method of random sequence generation sufficiently [7][8][9][11][12][13] . Hence, hey were considered a low risk of bias.One study was marked unclear due to a lack of sufficient data [10] .Random allocation concealment was reported in detail in five studies, and the risk of bias was marked as low in these studies [7][8][9]11,13] .Two studies showed some concerns and hence were marked as having a high risk of bias [10,12] .Most of our included studies reported the blinding methods used for the participants, personnel, or outcome assessment, so they were considered to have a low risk of bias.No study has any missing data. Regading other sources of bias, all studies were considered as having a low risk of bias.The quality assessment for observational studies, carried out by NOS, showed that none of the studies scored 8.
The quality assessment of the 7 RCTs and 19 non-randomized prospective studies is presented in Table 2.

Publication bias
The publication bias between studies is illustrated in Figure 2.

Quantitative analysis
The final 23 articles were analyzed for our desired outcomes.Some studies reported our desired outcomes more than once.

Primary outcomes
Mortality (Figure 3A-D) illustrates the outcome.
1 year: Four of our included studies had this outcome [8,12,16,25] .There were no statistically significant differences between BEV and SEV for stroke after a year.(OR = 1.018; 95% CI: 0.834-1.242;P = 0.864), and evidence of heterogeneity was found among the included studies (I 2 = 32.4%;P = 0.218) (Figure 4). 5 years: Only two studies reported and compared 5-year stroke adverse events between both groups; hence, no analysis was done.
5 years: Only two studies reported and compared 5-year hospitalization between both groups; hence, no analysis could be performed.
1 year and 5 years: Only two and one of our included studies had 1-year and 5-year outcomes, respectively; hence, no analysis was done.
1 year and 5 years: Only two and one of our included studies had 1-year and 5-year outcomes, respectively; hence, no analysis was done.
1 year and 5 years: Only one study had evaluated one year of AKI incidence, warranting no quantitative meta on it.Myocardial infarction (MI).Figure 9 (A,B,C,D) illustrates this outcome.
1 year: Three of our included studies had this outcome [8,23,25] .There were no statistically significant differences between BEV and SEV for stroke after a year.(OR = 1.027; 95% CI: 0.351-3.006;P = 0.961), and no evidence of heterogeneity was found among the included studies (I 2 = 0; P = 0.931).(Fig. 3) 5 years: Only two studies reported and compared 5-year MI between both groups; hence, no analysis was done.

Discussion
During the last few decades, minimal techniques have taken the world by storm due to numerous advantages with minimal blood loss, fewer complications, and shorter hospital stays, among many others [33] .In the context of Aortic stenosis, transcatheter is being compared and studied against surgical valve replacement [3,34] .Multiple meta-analyses have evaluated the BEV and SEV for different outcomes in transcatheter aortic replacement.However, we found that most studies evaluated either short-term outcomes, procedural success, or aortic function restoration, while one study compared long-term and short-term outcomes [34][35][36][37][38] .Our paper is the first to consider combining and subgrouping outcomes at a particular time frame for analysis.
Our analysis also focused on outcomes between BEV and SEV without restriction for the type of study and stratification only based on outcome.Hence, it may be an analysis with the most significant number of studies.Our first outcome of interest mortality was significant and favored BEV over SEV for at least three subgroups.This was contrary to previous literature that found none of the valve systems superior to another [35,37] .However, a recently published analysis favored BEV regarding short-term overall mortality [38] .Notable is the point that while our study had no statistical significance for a year's mortality, the overall mortality favored BEV, making it a better choice.For our next outcome, stroke, none of the groups were favored overall or any of the subgroup analyses.This was in line with previous investigations and results [36,37] .This could lead to the hypothesis that if stroke is not the leading cause of mortality after TAVR in any group, other non-apparent causes need investigation.Our subsequent leading outcome of interest, hospitalization, was not a part of many previous investigations.However, we found it statistically significant as an overall outcome and favoring BEV.This could point out that fewer complications were associated with BEV in general.Even if there were more, the recovery time was faster, benefiting the patients undergoing this procedure overall.
For PPM, our outcomes and their results were in line with previously reported literature.Our analysis favored BEV for having fewer incidents of pacemaker implantation compared to SEV [37,38] .However, none of the groups were superior for the rest of our outcomes (Bleeding Risk, AKI, and MI).This can also explain that the mortality difference seen and found in our analysis and previous literature may be a complex attribute and may be related to procedural failure, iatrogenic or individual patient comorbidities.However, this leaves room for future research to determine the ultimate leading causes of mortality when general complications that follow surgery are non-significant.
Despite the considerable attention surrounding TAVR and its subtypes, only a few of our examined outcomes exhibited statistical significance.Hence, it sheds light on the fact that choosing a specific valve type needs more than just looking into its features.The healthcare providers may want to investigate availability, affordability, technical considerations, and factors influencing postoperative management to optimize outcomes, make informed decisions, and minimize the need for additional interventions.
Our paper has some limitations.The first limitation is the involvement of specific companies in manufacturing each type of valve, introducing potential sources of conflict.Secondly, one of our included studies, Deharo et al. [16] , had a large sample size compared to other groups, influencing results.The study focused on specific outcomes, including mortality, stroke, hospitalization, MI, bleeding, AKI, and pacemaker insertion to maintain clinical relevance and statistical power.This approach was chosen due to resource constraints and the need to manage heterogeneity among included studies.Consequently, other essential factors, such as vascular complications, infections, and surgical success, were not analyzed.While this streamlined focus enhances the applicability of the findings to clinical practice and aligns with existing literature, it is essential to recognize that a more comprehensive assessment of all possible outcomes would offer a broader perspective on TAVR outcomes.Additionally, most of our included studies were observational.While observational studies provide valuable real-world data, they inherently carry limitations related to potential biases and confounding variables.The absence of RCTs may limit the ability to establish causal relationships between valve type (self-expanding or balloonexpandable) and the selected outcomes.Therefore, while our findings offer valuable insights, they should be interpreted in the context of the inherent limitations of observational study designs.

Conclusion
In conclusion, our analysis accurately evaluates the outcomes of BEV vs. SEV.While our findings suggest potential advantages of BEV in terms of mortality and fewer hospitalizations, further research is still warranted to evaluate the two options.Particularly considering the non-significant results for other outcomes, cost-effectiveness, and patient-reported outcomes to inform clinical decision-making and enhance patient care in this surgical domain.

Figure 1 .
Figure 1.Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart of literature search.

Table 2
Risk of Bias for RCTs