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 (8–10). Thus, the questions regarding the procedural and mid-term 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.

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).

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, 19–22). 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).

To our knowledge, this study comprehended the first meta-analysis 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 30-day 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 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, 19–22). Notably, three of them reported no procedural death or 30-day death for the patients with Sievers type 0 BAV (20–22). 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.

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.

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

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 meta-analysis and drafted the manuscript with a complete review by ZW and WL. All have authors read and approved the final manuscript.

The National Key Research and Development Program of China (2017YFC0908800), the Beijing Municipal Administration of Hospitals' Mission plan (SML20180601), the Capital's Funds for Health Improvement and Research (FH 2020-2-2063) (KM200910025012), the Beijing Municipal Natural Science Foundation (7202041), and the Beijing Municipal Health Commission (jing19-15).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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