When Early Success Is Not the End Point: Reassessing Transcatheter Therapy in Bicuspid Aortic Valve Stenosis

The emergence and rapid widespread growth of transcatheter aortic valve implantation (TAVI) ranks among the most transformative paradigm shifts in contemporary lifetime management of aortic valve disease management. ¹ , ² TAVI is undoubtedly the most dominant procedure performed across a spectrum of all surgical risk profiles of patients with tricuspid aortic stenosis, catalyzing changes in contemporary guidelines and clinical practice. ³ , ⁴ This growth has been largely due to an accumulation of a robust body of randomized evidence demonstrating noninferiority—and for some selected outcomes, a signal toward superiority of TAVI compared with surgical aortic valve replacement (SAVR). ¹ , ² Yet this success has fostered an implicit assumption that what holds true for tricuspid anatomy must also apply to bicuspid disease in the context of aortic stenosis.

Bicuspid aortic valve (BAV) stenosis, however, represents a fundamentally different and heterogenous disease rather than a simple anatomical variant. ⁵ , ⁶ In addition to being excluded from all pivotal randomized trials comparing TAVI versus SAVR, patients with BAV pose unique challenges, including asymmetric leaflet calcification, elliptical annular geometry, and a high prevalence of associated aortopathy. ⁵ , ⁶ , ⁷ , ⁸ These features directly affect the procedural success of valve deployment, sealing, and clinically, long‐term durability, rendering direct extrapolation from tricuspid data scientifically tenuous and clinically risky.

Despite these uncertainties, clinical practice has appeared to move ahead of the evidence. In many centers, TAVI is increasingly offered to patients in their early 60s with bicuspid anatomy, often justified by procedural convenience, patient preference, and reassuring short‐term outcomes. ⁸ , ⁹ Yet this practice rests predominantly on early end points derived from registries and observational studies. For younger patients with long life expectancy, the clinically decisive questions—durability, late valve failure, and survival beyond the first several years—remain inadequately answered. The result is a widening gap between technological enthusiasm and evidentiary maturity. ³ , ⁹

It is within this context that the time‐to‐event meta‐analysis by Moscarelli and colleagues in this issue of the Journal of the American Heart Association (JAHA) merits close attention. ⁷ This meta‐analysis represents the largest and most methodologically rigorous time‐to‐event meta‐analysis to date comparing TAVI and SAVR in patients >60 years of age with BAV stenosis. Recognizing the limitations of fixed‐timepoint analyses, the authors reconstructed individual patient‐level data from published Kaplan–Meier curves across 39 studies, enabling direct longitudinal comparison of clinical outcomes. The primary analysis focused on 5 comparative, risk‐adjusted studies (TAVI: 5901; SAVR: 12427 patients). The primary end point was a composite of all‐cause mortality with or without stroke and unplanned rehospitalization, assessed over a truncated follow‐up of 48 months. A series of complementary analytical approaches—including landmark analysis, time‐varying hazard ratios (HRs), frailty‐adjusted Cox models, and restricted mean survival time—were employed to address patient heterogeneity and violations of proportional hazards.

Importantly, the study ¹⁰ highlighted 3 key aspects:

• TAVI was associated with a 62% higher hazard for the composite end point of death, stroke, or rehospitalization at 48 months (HR, 1.62 [95% CI, 1.46–1.79]; P<0.001).

• There appeared to be a time‐dependent treatment effect such that TAVI demonstrated an early procedural advantage that diminished and reversed after 6 months and persisted beyond 12 months in the landmark analysis.

• De novo pacemaker implantation was substantially higher after TAVI (12.6% versus 4.9%) in this heterogenous patient population although early mortality and stroke rates did not differ significantly between groups.

Collectively, these results challenge reliance on short‐term end points—standard in contemporary TAVR trials—as surrogates for long‐term benefit and suggest that early procedural success with TAVI may not translate into durable midterm advantage in bicuspid anatomy based on the time‐varying hazard analysis. The observed pattern—early benefit with subsequent attenuation—is biologically plausible in bicuspid anatomy. Asymmetric calcification and elliptical annular geometry may predispose transcatheter valves to nonuniform expansion and device‐annulus mismatch, altered leaflet kinematics, and paravalvular regurgitation. ⁵ , ¹¹ These differential mechanical factors may then accelerate leaflet stress, subclinical thrombosis, and structural valve deterioration, processes unlikely to manifest within the first year but increasingly relevant thereafter in TAVI. In contrast, SAVR allows direct annular decalcification, symmetric valve implantation, and concomitant aortic repair when indicated, factors that may confer durability advantages not captured by early outcomes in contemporary studies.

DURABILITY: THE UNRESOLVED CORE QUESTION

Durability remains the central unresolved issue in BAV intervention. To date, no randomized controlled trials have compared TAVI and SAVR specifically in bicuspid aortic stenosis. All available data derive from observational registries and retrospective analyses, and the longest available durability data for TAVI in bicuspid anatomy extend to ∼5 years only. These data demonstrate acceptable midterm structural valve performance but reveal important signals regarding durability, particularly in younger patients and those with specific anatomical phenotypes.

Moscarelli et al.'s study findings align with and extend prior comparative data. In the largest multicenter registry, cumulative incidence of moderate‐to‐severe structural valve deterioration reached 8% at 5 years, with bioprosthetic valve failure exceeding 6%. ¹² A recent meta‐analysis of 15 studies (n=22 085) similarly demonstrated superior long‐term survival for SAVR beyond 6 months in patients with BAV. ¹³ The Mehaffey et al. Medicare analysis (2018–2022) found TAVI associated with higher 5‐year mortality (HR, 1.49) and stroke (HR, 1.35) despite lower procedural mortality. ¹⁴ The NOTION‐2 (Nordic Aortic Valve Intervention 2) trial, although showing overall similar 3‐year outcomes between TAVI and SAVR in low‐risk patients, noted a nonsignificant trend toward worse outcomes with TAVI specifically in the subgroup with BAV (20.4% versus 7.8% composite events; HR, 2.9). ¹⁵ Other studies report similar rates of structural deterioration in bicuspid and tricuspid anatomy but with limited follow‐up and low absolute event counts. ¹⁶

Nonetheless, the findings contrast with data from tricuspid aortic stenosis, where the PARTNER 3 (Placement of Aortic Transcatheter Valves 3) trial demonstrated similar 7‐year outcomes between TAVI and surgery in low‐risk patients. ² This discrepancy likely reflects the unique anatomical challenges of bicuspid valve, which may directly influence the long‐term durability. ⁷ , ¹⁷ Encouragingly, newer‐generation devices appear to perform better. The STABILITY (Bicuspid TAVI Durability) registry reported only 4% hemodynamic valve dysfunction at 4 years, with very low reintervention rates. ¹⁸ However, these data remain insufficient for patients in their 60s with anticipated survival measured in decades.

Age‐dependent risk is particularly concerning. Younger bicuspid patients demonstrate significantly higher reintervention rates following TAVI, mirroring the well‐established age‐related decline in durability of surgical bioprostheses. ¹⁹ For patients with 15 to 20 years of life expectancy, the absence of data beyond 5 to 7 years represents a critical evidentiary void.

IMPLICATIONS FOR TRIAL DESIGN AND CLINICAL PRACTICE

Current American College of Cardiology/American Heart Association guidelines assign TAVI only a Class IIb recommendation for bicuspid aortic stenosis, emphasizing that it “may be considered” at Comprehensive Valve Centers after careful consideration of patient‐specific factors. ⁴ The American Association for Thoracic Surgery consensus guidelines similarly emphasize individualized decision‐making, particularly given the frequent need for concomitant aortic repair in bicuspid patients. ²⁰ The findings of Moscarelli et al. have important clinical implications and further reinforce the urgent need for dedicated randomized trials in BAV stenosis. Equipoise may likely exist in patients aged 70 to 75 years with intermediate surgical risk and favorable BAV morphology. However, any such trial will require some form of standardized computed‐tomography‐based preoperative anatomical stratification (given the heterogeneity in clinical phenotypes) and will need to employ clinical end points that extend beyond 5 to 10 years (given the time‐varying nature of clinical efficacy).

Until such data are available, expansion of TAVI into younger bicuspid cohorts should proceed cautiously and systematically based on a comprehensive heart team evaluation, keeping in mind the overall life expectancy of these patients in the context of lifetime management of aortic valve disease. Thus, for patients with favorable surgical anatomy and long life expectancy, SAVR could potentially be the reference standard. On the other hand, TAVI may remain reasonable for older patients or those with prohibitive surgical risk and favorable bicuspid morphology.

In conclusion, Moscarelli and colleagues provide a timely and methodologically rigorous reminder that early success is not synonymous with durable benefit in the management of patients with BAV. By shifting attention from short‐term procedural metrics to longitudinal risk, their analysis challenges complacency and reframes decision‐making in bicuspid aortic valve stenosis in the current era. Until long‐term randomized data become available, restraint, disciplined patient selection, and a commitment to durability must guide the management of BAV disease (Figure 1).

Figure 1. Temporal tradeoffs in TAVI versus SAVR in bicuspid aortic valve stenosis.

SAVR indicates surgical aortic valve replacement; and TAVI, transcatheter aortic valve implantation.

Disclosures

None.