Transcatheter aortic valve replacement (TAVR) has evolved from a novel technology to an established therapy for high-risk patients with symptomatic severe aortic valve stenosis (AS). Although randomized trials have established TAVR as the standard treatment in inoperable patients and a reasonable option in intermediate- or high-surgical-risk patients, bicuspid AS has been excluded from these major trials.^1-4 This was mainly attributable to concerns about challenging anatomic features of bicuspid AS for TAVR including the following:

1. A larger annulus, severe and asymmetric leaflet calcification, or presence of calcified raphe that may hinder valve positioning and expansion and lead to significant paravalvular regurgitation or annulus rupture (Figure 1)
2. Concomitant aortopathy with a potential increased risk of aortic dissection or rupture during long-term follow-up
3. Long-term durability of transcatheter heart valves in younger patients with longer life expectancy

However, accumulated experience and advances in device technology have led to the increased off-label use of TAVR for bicuspid AS.⁵ Aortic valve structure in 932 patients with operatively excised stenotic aortic valves revealed that the prevalence of bicuspid AS was higher in younger populations: 60% in 61-70 years, 42% in 71-80 years, and 28% in 81-90 years.⁶ Given the expanding indication of TAVR into moderate surgical risk, the clinical outcomes of TAVR in bicuspid AS warrant special attention.

Figure 1

The initial report by Wijesinghe et al. showed the feasibility of TAVR in 11 patients with bicuspid AS. Edwards SAPIEN valves (Edwards Lifesciences; Irvine, CA) were implanted successfully in all patients with significant hemodynamic improvement, but 2 patients (18.2%) had moderate paravalvular leak.⁷ Mylotte et al. showed the feasibility of TAVR in bicuspid AS using the first-generation balloon-expandable valves (SAPIEN) or self-expanding valves (Medtronic CoreValve [Medtronic, Dublin, Ireland).⁸ Paravalvular leak ≥ grade 2 occurred in 28.4% of patients (19.6% with SAPIEN vs. 32.2% with CoreValve; p = 0.11). One-year mortality was 17.5%, without significant difference between the valves (20.8% with SAPIEN vs. 12.5% with CoreValve; log rank p = 0.12). Similar to what has been observed in tricuspid AS, the use of multidetector computed tomography (MDCT) was associated with a lower rate of significant paravalvular leak (odds ratio: 0.19; 95% confidence interval: 0.08-0.45; p < 0.0001). Furthermore, MDCT showed the higher accuracy to detect bicuspid AS compared with echocardiography.⁹

Regarding the diagnosis and classification, based on pathological findings, Sievers classification has been widely accepted in the current practice.¹⁰ In the TAVR era, a preprocedural MDCT has become standard, so a preprocedural diagnosis of bicuspid AS has gained considerable attention. With accumulation of experience and knowledge, MDCT assessment of the aortic valve has confirmed and highlighted the great variety of bicuspid AS morphology. Accordingly, Hasan et al. recently proposed a new classification of bicuspid AS,¹¹ in which bicuspid AS was classified according to the number of raphe and commissures with high-resolution MDCT images. The clinical utility and impact of this new classification need to be evaluated in future studies.

Despite the higher rate of significant paravalvular leak and lower device success rate in bicuspid AS after SAPIEN and CoreValve implantation, improved outcomes using the new-generation devices (SAPIEN 3 or LOTUS Valve System [Boston Scientific; Marlborough, MA]) were reported.^12,13 In 51 patients with bicuspid AS treated with SAPIEN 3, no patients had second valve implantation or paravalvular leak ≥ moderate. Similarly, the Bicuspid Aortic Stenosis Following Transcatheter Aortic Valve Replacement Registry showed lower rate of paravalvular leak ≥ moderate and higher device success rate with the new-generation devices compared with the early-generation devices (0.0% vs. 8.5%; p = 0.002). The external skirt of SAPIEN 3 allows effective sealing, which may mitigate the morphological challenges of bicuspid AS. Similarly, the mechanical expanding LOTUS Valve System with adaptive sealing along with retrievability and repositioning may facilitate optimal positioning and prevent paravalvular leak.

In terms of long-term survival data in the bicuspid AS population, reported studies are limited by the clear differences in age and comorbidities that favor the bicuspid AS population compared with tricuspid AS population. In this context, a recent study compared bicuspid and tricuspid AS populations using propensity-score matching and evaluated the outcomes between the two groups. Compared with those with tricuspid AS, patients with bicuspid AS undergoing TAVR with early-generation devices more often developed adverse procedural events, but there were no significant differences between groups in procedural complications with new-generation devices (Figure 2). The cumulative all-cause mortality rates at 2-year follow-up were comparable between bicuspid and tricuspid AS groups (17.2% vs. 19.4%; p = 0.28) (Figure 3).¹⁴

Figure 2

Figure 3

Although these are encouraging data, there remain issues to be resolved. The association between outcomes of TAVR and the morphology of bicuspid AS should be evaluated. When stratified according to the bicuspid AS morphology, the rates of annulus rupture after TAVR using the balloon-expandable valves were numerically high in type 1 bicuspid AS with calcified raphe (Figures 4-6). Due to the sealing skirt, a lower degree of oversizing is required when using the SAPIEN 3 compared with the SAPIEN XT. Nevertheless, the annulus rupture occurred in 2.3% of patients when using the SAPIEN 3, which suggests that simple application of traditional annulus measurement and device sizing are not necessarily appropriate in treating bicuspid AS.

Figure 4

Figure 5

Figure 6

Furthermore, concomitant aortopathy (if present) should be considered when treating bicuspid AS. The risk of aortic dissection or rupture is greater in patients with a bicuspid aortic valve than in the general population, and that risk increases with aging-related progressive aortic dilation and degeneration.^15,16 According to the updated guidelines, replacement of the ascending aorta is reasonable in patients with bicuspid aortic valve who are undergoing surgical aortic valve replacement when the diameter of ascending aorta is greater than 4.5 cm (class of recommendation IIa; level of evidence C-EO [consensus of expert opinion based on clinical experience]).¹⁷ These recommendations were based on previous studies including patient population with younger age, fewer baseline comorbidities, and longer life expectancy. Therefore, future studies are needed to evaluate the incidences of ascending aorta aneurysm or aortic dissection/rupture in patients with bicuspid AS undergoing TAVR. Finally, limited data exist regarding the durability of transcatheter heart valves in the bicuspid AS population. Due to unfavorable anatomy, there is a concern about under-expansion of valves, which potentially leads to structural valve failure. Future studies are awaited to evaluate the long-term durability of transcatheter valves in the bicuspid AS population.

In conclusion, procedural challenges of TAVR in bicuspid AS were observed with early-generation devices, but improved procedural outcomes were achieved with the new-generation devices. Cumulative 2-year all-cause mortality rates of patients with bicuspid AS were comparable to those with tricuspid AS. However, limited data exist regarding long-term survival and hemodynamic data. Therefore, careful consideration is required during the decision-making process to treat patients with bicuspid AS, particularly for younger patients with long life expectancy and unfavorable anatomy including a calcified raphe and/or a dilated ascending aorta.

References

1. Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597-607.
2. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364:2187-98.
3. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or Surgical Aortic-Valve Replacement in Intermediate-Risk Patients. N Engl J Med 2016;374:1609-20.
4. Reardon MJ, Van Mieghem NM, Popma JJ, et al. Surgical or Transcatheter Aortic-Valve Replacement in Intermediate-Risk Patients. N Engl J Med 2017;376:1321-31.
5. Hira RS, Vemulapalli S, Li Z, et al. Trends and Outcomes of Off-label Use of Transcatheter Aortic Valve Replacement: Insights From the NCDR STS/ACC TVT Registry. JAMA Cardiol 2017;2:846-54.
6. Roberts WC, Ko JM. Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves in adults having isolated aortic valve replacement for aortic stenosis, with or without associated aortic regurgitation. Circulation 2005;111:920-5.
7. Wijesinghe N, Ye J, Rodés-Cabau J, et al. Transcatheter aortic valve implantation in patients with bicuspid aortic valve stenosis. JACC Cardiovasc Interv 2010;3:1122-5.
8. Mylotte D, Lefèvre T, Søndergaard L, et al. Transcatheter aortic valve replacement in bicuspid aortic valve disease. J Am Coll Cardiol 2014;64:2330-9.
9. Hayashida K, Bouvier E, Lefèvre T, et al. Transcatheter aortic valve implantation for patients with severe bicuspid aortic valve stenosis. Circ Cardiovasc Interv 2013;6:284-91.
10. Sievers HH, Schmidtke C. A classification system for the bicuspid aortic valve from 304 surgical specimens. J Thorac Cardiovasc Surg 2007;133:1226-33.
11. Jilaihawi H, Chen M, Webb J, et al. A Bicuspid Aortic Valve Imaging Classification for the TAVR Era. JACC Cardiovasc Imaging 2016;9:1145-58.
12. Perlman GY, Blanke P, Dvir D, et al. Bicuspid Aortic Valve Stenosis: Favorable Early Outcomes With a Next-Generation Transcatheter Heart Valve in a Multicenter Study. JACC Cardiovasc Interv 2016;9:817-24.
13. Yoon SH, Lefèvre T, Ahn JM, et al. Transcatheter Aortic Valve Replacement With Early- and New-Generation Devices in Bicuspid Aortic Valve Stenosis. J Am Coll Cardiol 2016;68:1195-205.
14. Yoon SH, Bleiziffer S, De Backer O, et al. Outcomes in Transcatheter Aortic Valve Replacement for Bicuspid Versus Tricuspid Aortic Valve Stenosis. J Am Coll Cardiol 2017;69:2579-89.
15. Michelena HI, Khanna AD, Mahoney D, et al. Incidence of aortic complications in patients with bicuspid aortic valves. JAMA 2011;306:1104-12.
16. Itagaki S, Chikwe JP, Chiang YP, Egorova NN, Adams DH. Long-Term Risk for Aortic Complications After Aortic Valve Replacement in Patients With Bicuspid Aortic Valve Versus Marfan Syndrome. J Am Coll Cardiol 2015;65:2363-9.
17. Hiratzka LF, Creager MA, Isselbacher EM, et al. Surgery for Aortic Dilatation in Patients With Bicuspid Aortic Valves: A Statement of Clarification From the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016;67:724-31.

Keywords: Heart Valve Diseases, Aortic Valve, Transcatheter Aortic Valve Replacement, Multidetector Computed Tomography, Odds Ratio, Propensity Score, Life Expectancy, Confidence Intervals, Expert Testimony, Bicuspid, Dilatation, Off-Label Use, Heart Valve Diseases, Aortic Valve Stenosis, Heart Valve Prosthesis, Calcinosis, Echocardiography, Registries, Comorbidity, Aorta, Hemodynamics, Aging, Aneurysm, Dissecting

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