Transcatheter Aortic Valve Implantation in Sievers Type 0 vs. Type 1 Bicuspid Aortic Valve Morphology: Systematic Review and Meta-Analysis

Background: Transcatheter aortic valve implantation (TAVI) has achieved satisfactory outcomes in the selected patients with bicuspid aortic valve (BAV), predominately type 1 BAV (~90%). However, there are few reports about the safety and efficacy of TAVI in type 0 BAV. Therefore, in the current study, we aimed to compare procedural and 30-day outcomes after TAVI between type 0 and type 1 BAV. Methods: Studies comparing the outcomes of TAVI in Sievers type 0 vs. type 1 BAV were retrieved from PubMed, EMBASE, Cochrane Library, and Web of Science from inception to May 2021. The data were extracted regarding the study characteristics and outcomes. The odds ratios (ORs) with 95% CIs were pooled for procedural and 30-day outcomes. Results: Six observational studies were included with determined type 0 BAV in 226 patients and type 1 BAV in 902 patients. The patients with type 0 BAV were slightly younger, had larger supra-annular structure, and more frequently implanted self-expanding prosthesis compared with type 1 BAV. In the pooled analyses, the patients with type 0 BAV had a similar incidence of procedural death (OR = 2.6, 95% CI 0.7–10.3), device success (OR = 0.6; 95% CI 0.3–1.3), and ≥ mild (OR = 0.8; 95% CI 0.4–1.6) or moderate (OR = 0.9, 95% CI 0.4–1.8) paravalvular leak, whereas significantly higher mean aortic gradient (mean difference = 1.4 mmHg, 95% CI 0.03–2.7) and increased coronary compromise risk (OR = 7.2; 95% CI 1.5–34.9), compared with type 1 BAV. Meanwhile, the incidence of death (OR = 1.2; 95% CI 0.5–3.1), stroke (OR = 0.5; 95% CI 0.1–2.4), and new pacemaker (OR = 0.6; 95% CI 0.2–2.2) at 30 days were not significantly different between the BAV morphologies (p > 0.05). The treatment effect heterogeneity across the studies for the above outcomes were low. Conclusions: The patients with type 0 BAV appear to have similar short-term outcomes after TAVI compared with type 1 BAV. Whereas, TAVI for type 0 BAV aortic stenosis might lead to an elevated coronary obstruction risk and suboptimal aortic valvular hemodynamics.


INTRODUCTION
Transfemoral transcatheter aortic valve implantation (TAVI) is confirmed as a safe and effective alternative to surgical aortic valve replacement (SAVR) for symptomatic, elderly patients with severe aortic stenosis (AS), regardless of the estimated surgical risk (1). However, for selected severe patients with AS and bicuspid aortic valve (BAV), TAVI has only presented a class 2b guidelines recommendation since these patients were excluded from the previous randomized controlled trials (1). Different reasons to exclude the patients with BAV in the prior trials include young age, low surgical risk, and the challenging aortic valvular complex anatomies (e.g., fused calcified raphe, asymmetric leaflet calcification, and coexisting aortopathy) (2). Recently, due to the newest generation devices and refined techniques, TAVI in the selected patients with BAV has become more prevalent, and achieved optimal procedural and short-term outcomes, except for a small, but notable, stroke and paravalvular leak (PVL) risk compared with the tricuspid aortic valves (3,4). Meanwhile, the US Food and Drug Administration has removed the precaution from commercial labeling regarding TAVI in the patients with BAV using SAPIEN-3 (Edwards Lifesciences Inc., CA, USA) or Evolut-R/Pro (Medtronic Inc., Dublin Ireland) (5,6).
However, BAV can present different morphologies. According to the Sievers classification, the BAV phenotypes are categorized by the raphe number (0, 1, and 2), with BAV type 1 as the most common (2,7). The Sievers type 0 BAV morphology, with the two commissures opening in a significant elliptical fashion, was under-represented (∼10%) in the previous multicenter analyses (8)(9)(10). Thus, the questions regarding the procedural and midterm outcomes of TAVI in type 0 BAV remain unanswered. Therefore, in the present systematic review and meta-analysis, we aimed to investigate whether BAV morphology (e.g., Sievers type 0 vs. type 1) can affect the TAVI results.

METHODS
This study was performed following the Meta-Analyses of Observational Studies in Epidemiology (MOOSE) protocol (11) and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist (12).

Search Strategy, Study Selection, and Eligibility Criteria
According to the Population, Interventions, Comparison, Outcome and Study Design (PICOS) strategy, the studies were enrolled if the following criteria were met: (1) the population consisted of the patients with BAV that underwent TAVI; (2) there was an exposure (or intervention) group with Sievers type 0 BAV; (3) there was an exposure (or comparator) group with Sievers type 1 BAV; (4) the outcomes of interest included inhospital, 30-day and 1-year outcomes; and (5) the comprehended observational studies. We searched for the published studies in PubMed/MEDLINE, EMBASE, Cochrane Library, and Web of Science from inception to May 2021. We used the Medical Subject Headings terms and free text to describe the following keywords: (1) "Transcatheter Aortic Valve Implantation" or "Transcatheter Aortic Valve Replacement, " (2) "Bicuspid Aortic Valve" or "Bicuspid Aortic Valve Disease, " (3) "Aortic Valve Stenosis" or "Aortic Stenosis, " and (4) "Bicuspid Aortic Valve Stenosis" or "Bicuspid Aortic Stenosis." The search strings included: (1) AND (2), (1) AND (2) AND (3), and (1) AND (4). Some studies could have used different BAV morphological classification systems [e.g., (13,14)] and we only included those in which the BAV classification could be translated to Sievers and Schmidtke (7). We excluded the case reports, animal studies, or studies published in non-English languages. The eligibility and quality of each study were assessed by the two independent investigators, and the discrepancies were solved by consensus.

Data Extraction, Outcomes, and Bias Risk Assessment
We collected the following data from each study: study design, the patient characteristics, the imaging findings, the procedural details, and in-hospital, 30-day, and 1-year outcomes. The primary outcome of this study was 30-day mortality. The secondary outcomes consisted of other 30-day outcomes [stroke, life-threatening bleeding, major vascular complication, acute kidney injury (AKI) stage 2-3, and new permanent pacemaker (PPM)]; 1-year outcomes (mortality, cardiac mortality, and stroke); and in-hospital outcomes [procedural death, need of > 1 transcatheter heart valve (THV), cardiac tamponade, aortic root injury, coronary compromise, conversion to surgery, postdilatation, new PPM, device success, and ≥ mild or moderate PVL at discharge echocardiography]. The outcomes were defined in line with the Valve Academic Research Consortium 2 (VARC-2) criteria (15). It is worth mentioning that the outcomes data were extracted only from the patients with an established Sievers type 0 or type 1 BAV anatomy. The bias risk of each study was systematically assessed using the Newcastle-Ottawa scale criteria (16).

The Statistical Analyses
Effect summary measures are presented as the mean differences (MDs) or odds ratios (ORs) with their 95% CIs. We combined the summary measures using the random-effects Mantel-Haenszel method (17). The χ 2 and I 2 tests were used to assess the heterogeneity, with a p < 0.1 indicating statistical significance for heterogeneity and I 2 > 50% for important heterogeneity (18). The subgroup analyses were performed in studies (1) reporting cardiac death or disabling stroke, (2) using earlygeneration THV (e.g., SAPIEN, SAPIEN XT, and CoreValve) vs. new-generation THV (e.g., SAPIEN-3, Evolut-R, and Evolut-Pro), and (3) using self-expanding valve (SEV) + balloonexpandable valve (BEV) vs. SEV. A sensitivity analysis was performed by removing each study from the pooled analysis in turn and examining if there was a change in the pooled results. A two-tailed p < 0.05 was considered statistically significant. The statistical analyses were performed using the Review Manager software (version 5.3. Cochrane Collaboration; Copenhagen, Denmark).

RESULTS
The inclusion flow chart of the current study is shown in Figure 1. Six studies (1,239 patients) were enrolled to compare the procedural and clinical outcomes of TAVI between the Sievers type 0 and type 1 BAV (8,13,(19)(20)(21)(22). The bias risk of the enrolled studies was generally low based on the Newcastle-Ottawa scale criteria ( Table 1). Multi-detector CT (MDCT) was  used for BAV diagnosis in most of the patients, with 226 patients with determined Sievers type 0 BAV and 902 patients with type 1 BAV ( Table 2).

The Baseline and Procedural Characteristics Between Sievers Type 0 and Type 1 BAV
The clinical and imaging characteristics were available for 116 patients with the Sievers type 0 BAV and 455 with type 1 BAV (Tables 3, 4). Briefly, the mean overall age of patients was 75.7 years and 39% were female. Most of the patients had New York Heart Association (NYHA) functional class III-IV (62.5%) and low society of thoracic surgeons predicted the risk of mortality (mean score of 3.7%). The patients with type 0 BAV were slightly younger (MD = −1.4 years, p = 0.08) and had slightly lower ejection fraction (MD = −3.9%, p = 0.08) compared with type 1 BAV. Notably, the patients with type 0 BAV had markedly smaller aortic valve area (MD = −0.07 cm 2 , p < 0.01), larger sino-tubular junction (STJ) diameter (MD = 1.9 mm, p < 0.01), and height (MD = 2.4 mm, p < 0.01), as well as larger ascending aorta diameter at 40 mm from the annulus (MD = 1.7 mm, p < 0.01), compared with type 1 BAV. Meanwhile, the patients with type 0 BAV had larger left (MD = 1.6 mm, p < 0.01) and right (MD = 1.2 mm, p = 0.04) coronary take-offs compared with type 1 BAV. The TAVI procedural details were available for 156 patients with Sievers type 0 BAV and 790 with type 1 BAV (Table 5). Overall, the conscious sedation (68.9%) and balloon pre-dilation (73.0%) were commonly used. Most of the patients (90.0%) had transfemoral access and nearly half (50.8%) implanted SEV. It is worth noting that, compared with type 1 BAV, the patients with type 0 BAV were less likely to implant BEV (OR = 0.5, 95% CI 0.2-0.9), and numerically more frequently received SEV (OR = 2.2, 95% CI 0.9-4.8).
One-year outcomes were available in only one study (22), showing no difference in all-cause mortality, cardiac mortality, and stroke between the two BAV phenotypes (p > 0.05).
The Subgroup Analyses Between the Sievers Type 0 and Type 1 BAV No significant differences in the procedural and 30-day outcomes between TAVI in the patients with type 0 and type 1 BAV were observed using either early-generation THV (e.g., SAPIEN, SAPIEN XT, and CoreValve) or new-generation THV (e.g.,   SAPIEN-3, Evolut-R, and Evolut-Pro) ( Table 7), and using either SEV + BEV or SEV ( Table 8).

DISCUSSION
To our knowledge, this study comprehended the first metaanalysis comparing the procedural and clinical outcomes of TAVI in the patients with Sievers type 0 vs. type 1 BAV. Our main findings were: (1) the incidence of most procedural outcomes was similar between the type 0 vs. type 1 BAV (i.e., procedural death, THV embolization, > 1 THV, cardiac tamponade, aortic root injury, conversion to surgery, balloon post-dilation, new PPM, device success, ≥ mild PVL, or ≥ moderate PVL). However, the patients with type 0 BAV were associated with markedly higher mean aortic gradient before discharge and increased coronary compromise risk compared with type 1 BAV. (2) No marked differences between the two BAV configurations were found for the following 30-day outcomes: death, cardiac death, stroke, disabling stroke, life-threatening bleeding, major vascular complication, AKI stage 2-3, or new PPM. Importantly, the treatment effect heterogeneity was consistently low across the studies for procedural and 30-day outcomes. (3) The subgroup analyses in the patients using different THV generations, different THV types, and different hard endpoints definitions were consistent with the aforementioned procedural and 30day outcomes. Bicuspid aortic valve is the most common congenital heart disease (1∼2% of the population) and represents the main AS cause in the patients under 65 years of age (24,25). Given the indications of TAVI expanding to the young patients   with AS, more patients with BAV can be encounter in the contemporary pre-TAVI workup. However, little is known about the correlation between the Sievers BAV phenotypes and the clinical manifestations and outcomes after TAVI. Data from a large international, multicenter registry (n = 2,118) showed that, compared with BAV with raphe, the patients with BAV without raphe (i.e., type 0 BAV) referring for cardiac surgery were younger, less likely to have dysfunctional aortic valves, whereas had similar Valsalva sinus, STJ, and ascending aorta diameters by ECGs (26). In contrast, we found, in 571 patients with BAV that underwent TAVI for severe AS, that patients with type 0 BAV were only slightly younger and had numerically lower ejection fraction compared with type 1 BAV. The patients with BAV in the present study appeared much older (75.7 vs. 47.0 years) and to have more frequently severe AS (100 vs. 19.6%) than the aforementioned surgical registry (26). Meanwhile, we found a significantly larger STJ diameter and height, as well as ascending aorta diameter at 40 mm from the annulus. In addition, Jilaihawi et al. showed that the mean Valsalva sinus diameter was larger in the type 0 BAV than type 1 (13). Consistently, these findings demonstrated that type 0 BAV was associated with a larger supra-annular structure than type 1 BAV. Regarding the TAVI procedure, the balloon pre-dilation proportion was high whereas varied among the different centers [93.1∼100% in two Chinese centers (19,20) and 36.6% in an international registry mainly compromising the European centers (22)]. Balloon valvuloplasty for BAV-AS is supposed to facilitate the TAVI delivery system crossing, improve prosthesis expansion, and judge prosthesis size selection and coronary obstruction risk in combination with aortography (2). However, routine balloon pre-dilation might increase procedural stroke (20), and the benefit of deploying a cerebral embolic protection device remains to be established in this scenario. In our present pooled analysis, the 30-day stroke risk was similar between the type 0 and type 1 BAV, although no patient had a 30-day stroke in the type 0 BAV group (8,13,22,23). Consistent with these findings, Fan et al. demonstrated a similar number and total volume of cerebral ischemic lesions in diffusion-weighted MRI after TAVI between the two BAV categories (20).
Interestingly, the patients with type 0 BAV seemed more likely to implant SEV than BEV. This might be explained by the fact that TAVI for BAV-AS using BEV was associated with more than a five-time higher annulus rupture risk than SEV (2.5% vs. 0, p < 0.001) (27). Moreover, type 0 BAV is uncommon in clinical practice, where the physicians might not be well-experienced with this specific aortic morphology and thus tend to frequently use SEV. Although TAVI for BAV-AS using SEV, compared with BEV, was associated with a higher tolerable error rate, it might also lead to an increased moderate or severe PVL risk, probably due to the decreased radial force of SEV (28). Moderate or severe PVL is a major concern in the early trials of performing TAVI in BAV (incidence ranging from 8 to 20%) (8,13). Fortunately, its incidence significantly decreased (<4%) due to a more precise aortic valve sizing by MDCT and the use of new-generation THV with an extra sealing skirt or re-capture property (22,23). In our analysis, although the mean aortic gradient on pre-discharge echocardiography was markedly higher in type 0 compared with type 1 BAV, this small difference on aortic gradient (MD = 1.35 mmHg) did not lead to the significant differences in the ≥ mild or ≥ moderate PVL incidence between the two BAV groups. It  Type 0  Type 1  Type 0  Type 1  Type 0  Type 1 Type 0 Type 1  Type 0  Type   is worth mentioning that the impact of prosthesis selection (BEV vs. SEV or early-vs. new-generation) on the procedural outcomes should be treated as hypothesis-generating at this time since we did not observe these impacts in our subgroup analysis. Although the patients with type 0 BAV tended to have larger supra-annular structures and higher coronary take-offs, we found that TAVI for type 0 BAV was associated with a significantly higher coronary compromise risk compared with type 1. Traditionally, the coronary obstruction predictors during TAVI include low coronary take-off, small Valsalva sinus and STJ, long aortic leaflet, and bulky calcification close to the coronary ostium. Recently, Heitkemper et al. found that the distance ratio from cusp to coronary ostium to coronary artery diameter (< 0.7) was superior to coronary ostium height (< 14 mm) and Valsalva    sinus diameter (< 30 mm) to predict coronary obstruction in TAVI, with 100% sensitivity and 95.7% specificity (29). Thus, predicting coronary obstruction during TAVI can be difficult, in particular, for the challenging BAV anatomies. Meanwhile, coronary access post-TAVI is important considering that the patients with BAV-AS are generally young and at low surgical risk. In this case, BEV with an intra-annular and lower-frame design can be more friendly than SEV allowing easier coronary access (30,31). Regarding hard endpoints after TAVI in type 0 vs. type 1 BAV, the data are scarce and inconsistent. Jilaihawi et al. found that the patients with bicommissural non-raphe-type (i.e., type 0) BAV had higher procedural mortality than bicommissural raphe-type (i.e., "anatomical" type 1) BAV (9.5% vs. 0, p = 0.047), although no significant difference was detected at 30 days (13). Similarly, Yousef et al. showed that type 1 BAV with left and right cusp fusion was associated with markedly lower procedural, 30-day, and 1-year mortality, compared with other valve variants (p ≤ 0.05) (9). However, these mortality differences were driven by just several cases from the above early small-scale studies. Conversely, no significant differences in procedural or 30-day mortality were detected between the Sievers type 0 vs. type 1 BAV in the other five enrolled studies (8,(19)(20)(21)(22). Notably, three of them reported no procedural death or 30-day death for the patients with Sievers type 0 BAV (20)(21)(22). Consistently, a similar mortality up to 5 years was demonstrated between the two BAV subsets in the patients receiving SAVR after adjusting for age, diabetes, and left ventricular ejection fraction (26). In line with these findings, we did not found marked differences in procedural death, 30-day all-cause death, or 30-day cardiac death between the two BAV morphologies in the pooled analysis.
In addition, our study has some limitations. The trials included were either small feasibility studies or large retrospective registries, with inconsistent inclusion and exclusion criteria, thus the selection bias was hardly avoidable. Most of the enrolled studies did not report calcification distribution on raphe or leaflet, or aortic annulus elliptic shape, unfavorable anatomies for TAVI in type 1, and 0 BAV (2,32). The absence of these data precluded further subgroup analyses. Additionally, TAVI prosthesis might be constrained and under expanded in the patients with BAV with an asymmetrical aortic valvular complex, followed by accelerated deteriorating over time (24). However, bioprosthesis durability after TAVI in type 0 vs. type 1 BAV remained unknown due to the short-term follow-up.

CONCLUSION
In the elderly severe AS population with low surgical risk, the patients with Sievers type 0 BAV seem to have higher mean aortic gradient and increased coronary obstruction risk, but otherwise similar procedural and 30-day outcomes after TAVI compared with type 1 BAV. However, the current patients with BAV that underwent TAVI were highly selected, and future studies should identify the BAV related optimal anatomies, refine sizing strategies, and best implantation techniques for TAVI.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

AUTHOR CONTRIBUTIONS
YD, YZha, and YZho proposed the idea for the study and finished the study design. YY and SJ retrieved studies, collected and extracted data with disagreements resolved by YG and WH. YD, HS, and KH performed the metaanalysis and drafted the manuscript with a complete review by ZW and WL. All have authors read and approved the final manuscript.