Transcatheter aortic valve replacement: A journey of two decades and beyond

The number of patients with calcific aortic stenosis (AS) is 9.4 million according to 2019 Global Disease Burden estimates, which will continue to increase as the population ages.[1] For the treatment of symptomatic severe AS, transcatheter aortic valve replacement (TAVR) has evolved to be a well-established option across all risk spectra, with a rapid growth of procedures worldwide. The rise of TAVR initiates the revolution of the management of valvular heart diseases, from patient surveillance, the staging of disease, the use of multimodality imaging, the concept of the Heart Team, new designs and iterations of devices to technical innovations and the discovery of unmet clinical needs. As a consequence of the global adoption of TAVR, geographical differences in the epidemiology of AS and patient characteristics have also been further identified. An examination of the changing patient population, current applications and breakthroughs, and remaining challenges are crucial for the future of this technique. Herein, we discuss the temporal utilization of TAVR, the accumulation of evidence and progress of devices, the selection of patients, and some ongoing topics concerning the improvement of TAVR. The adoption of TAVR. There are currently no effective medical therapies to stop the initialization and progression of AS. The management of AS patients generally requires routine follow-up of the severity of stenosis, the onset of symptoms from AS, and the occurrence of ventricular decompensation before invasive intervention of AS is deemed necessary. Indications for TAVR are expanding because of multiple randomized trials of TAVR vs. the gold-standard surgical aortic valve replacement (SAVR) [Figure 1]. From the landmark PARTNER series and CoreValve series trials, TAVR demonstrated noninferiority or even superiority in terms of death or stroke. In a recent meta-analysis that synthesized all newly available randomized data comparing TAVR to SAVR for the treatment of severe AS, it was found that across lower-risk trials (low and low/intermediate risk) but not for higher-risk patients, the early risk of all-cause death (up to one year) after TAVR was lower than that after SAVR (relative risk 0.67, P = 0.031), as well as the early risk of the composite of death or disabling stroke (relative risk 0.68, P = 0.014), but no differences were found after later follow-up.[2] For secondary clinical outcomes, TAVR was consistently associated with an increased risk of new permanent pacemaker implantation, more-than-mild paravalvular leak (PVL), and major vascular complications but a decreased risk of new-onset atrial fibrillation, acute kidney injury, and major bleeding in both lower- and higher-risk groups.[2] In addition to clinical parameters, the cost-effectiveness of TAVR has also been demonstrated in all risk spectra. In a recent analysis in low-risk patients (~40% of severe symptomatic AS population), TAVR provided both greater quality-adjusted life expectancy and lower overall costs than SAVR at the 2-year follow-up.[3]Figure 1: TAVR breakthroughs and ongoing concerns. AR: Aortic regurgitation; MR: Mitral regurgitation; MS: Mitral stenosis; SAVR: Surgical aortic valve replacement; SYNTAX: Synergy between percutaneous coronary intervention with taxus and cardiac surgery; TAVR: Transcatheter aortic valve replacement; TR: Tricuspid regurgitation.Given the above accumulation of evidence, the volume of TAVR has seen a dramatic increase over the past two decades. The annual number of TAVR procedures has been reported to surpass isolated and combined SAVR in several regions.[4] Moreover, the growth of TAVR cases also occurs in young patients. In patients aged <65 years, TAVR utilization increased 2.7-fold from 2015 to 2021 in the United States, reaching almost equal volumes as SAVR by 2021.[5] However, TAVR volume shows geographical heterogeneity due to national economic resources and investment in novel medical services, ranging from over to 0.3 per million 200 per million people.[6] Although the adoption of TAVR in Chinese mainland relatively lagged behind that of the Western world, increasing momentum has been presented, particularly in recent years, with a total of 22,783 cases by October 2022. The evolution in the design of transcatheter heart valves and their delivery systems has reduced the incidence of PVL, conduction disturbances, and vascular complications and has achieved easier manipulation compared to early-generation devices. Some major improvements include the addition of sealing skirt, smaller sheaths, recapturing and repositioning features, larger cells of the stent frame to facilitate future coronary access, anticalcification technology of valve tissue, etc.[7] The current two mainstay types of transcatheter valves, i.e., balloon-expandable and self-expanding valves [Figure 1] have equivalent preferences in the majority of cases, although centers may have a dominant valve type. Overall, balloon-expandable devices provide greater opening force to secure circular expansion and minimize PVL but may be associated with a higher risk of annular rupture, while self-expanding devices are more prone to PVL and the need for a second device but may have better performance in terms of residual gradient. In the only randomized trial comparing balloon-expandable to self-expanding valves, i.e., the CHOICE trial, the two early-generation devices showed similar clinical outcomes at 1 year in high-risk patients, although a higher device success rate was achieved in balloon-expandable valves.[8] At 5 years, forward flow hemodynamics (larger prosthetic valve area and lower mean transprosthetic gradient) were significantly better in self-expanding valves.[9] The choice of the appropriate device remains a key component in procedural planning after carefully evaluating patient-specific anatomy, and long-term issues such as structural valve dysfunction and possible TAVR-in-TAVR or coronary interventions after TAVR should be involved in decision-making. Current application of TAVR. Classic TAVR candidates: As of now, the guidelines recommend the choice between TAVR and SAVR based on the evaluation of the Heart Team considering anatomy, life expectancy, and the issue of valve durability. The central question now switches from can we refer patients for TAVR to should we refer patients for TAVR. It has been recognized that although surgical risk ranging from extremely high to low has been covered in landmark randomized trials, the average age of enrolled patients remains approximately 80 years. As another important component in the decision-making between TAVR and SAVR, age plays a multilevel role in the lifetime management of issues such as future coronary access and the strategy of either TAVR-in-SAVR or TAVR-in-TAVR. The European guidelines now recommend TAVR for patients ≥75 years irrespective of surgical risk (Class 1), whereas the US guidelines recommend TAVR as an equal alternative to SAVR for patients ≥65 years (Class 1). The clinical and anatomical profiles of a straightforward transfemoral TAVR case will be similar to those enrolled in landmark randomized trials. Key anatomical exclusion criteria include unsuitable aortic annulus dimension for TAVR devices, unicuspid or bicuspid aortic valve, bulky calcified leaflets or severe calcification in the left ventricular outflow tract, noncalcified aortic valve, low take-off of coronary ostia combined with shallow sinus of Valsalva, unfavorable aortic root angulation, mechanical or bioprosthetic valve in any position, porcelain aorta, and unfavorable femoral access, while clinical exclusion criteria to be considered are concomitant valve diseases, aortic or coronary disease requiring surgery, left ventricular dysfunction, contraindication to antithrombotic therapies, recent acute myocardial infarction or cerebrovascular accident, severe comorbidities, and short estimated life expectancy [Figure 1].[10] The performance benchmark in these carefully selected patients has been set to a 30-day mortality as low as <1% and 1-year mortality as <3% in contemporary trials, with <5% major vascular complications and <1% disabling stroke.[11] Challenging scenarios: The two most frequently discussed unconventional scenarios of TAVR use are bicuspid aortic valve and pure aortic regurgitation. Due to their challenging anatomies, dedicated treatment strategies and devices have been developed in an attempt to achieve reproducible and effective clinical outcomes. Several propensity-matched studies, which diminish intrinsic baseline differences, have demonstrated equivalent 1-year mortality and incidence of moderate or severe PVL between bicuspid and tricuspid aortic valves using second-generation devices, as well as in low surgical risk patients.[12] However, current results are mainly derived from Sievers’ Type 1 bicuspid morphology, whereas the underpresented Type 0 subtype has recently been associated with a higher probability of elevated residual transvalvular gradients but a lower incidence of pacemaker implantation and PVL,[13] suggesting different behaviors among bicuspid subtypes. The expanded use of TAVR in patients with pure aortic regurgitation has been accelerated by specifically designed systems that protect against device embolization, where locators anchor onto the leaflets. In the ALIGN-AR trial, both safety and efficacy goals were met using the Trilogy system with low rates of valve embolization (2.2%), but the need for a permanent pacemaker post-TAVR was not low at 24.0%. Remaining issues. With more low-risk and relatively younger patients undergoing TAVR, the current focus is on whether we can secure long-term benefits. Two topics of interest are the use of cerebral embolic protection (CEP) devices and the durability of TAVR valves. Stroke risk persists in contemporary use of TAVR at approximately 2–3% and does not improve with experience, which remains a concern due to the substantial impact on quality of life, especially in younger patients. Although the incidence of large brain vessel occlusion is relatively low following TAVR, small ischemic lesions are frequently detected de novo on diffusion-weighted magnetic resonance imaging immediately after the procedure and are assumed to be due to embolism of calcific and thrombotic fragments.[14] The adjunct use of CEP devices during TAVR aims to decrease the incidence of stroke, but the results are controversial. The risk of stroke was not significantly different with the use of CEP (relative risk 0.88, 95% confidence interval 0.57–1.36, P = 0.566) in a meta-analysis including 6 randomized trials,[15] but in the recent PROTECTED TAVR trial with a large sample of 3000 patients, the use of CEP significantly decreased the incidence of disabling stroke, although not for all stroke as the primary endpoint.[16] One reasonable strategy to consider the use of CEP is to identify patients at high risk of TAVR-related stroke events. Risk models have been developed using covariates such as access to the procedure, prior stroke/transient ischemic attack, preprocedural shock, inotropes or mechanical assist devices, smoking, porcelain aorta, aortic valve calcium score, peripheral arterial disease, age, glomerular filtration rate, body surface area, prior valvular procedures, and prosthetic valve type. Further evidence of the efficacy of CEP will be provided by the British Heart Foundation PROTECT-TAVI trial planning 7730 enrollments.[17] We now have registry data reporting long-term durability up to 10 years. The cumulative incidence of structural valve deterioration (SVD) and valve failure is approximately 5%.[18] However, such studies had fewer than 20 patients left at 10 years, reflecting the high-risk profile of patients undergoing TAVR at its early phase. The devices used were of early generations. Thus, evidence of valve durability in the low-risk profile of younger patients receiving current generations of devices is lacking. Surgical bioprosthetic valves are believed to have excellent durability, with 55% freedom from explant for SVD at 20 years even in patients younger than 60 years in whom SVD is more common.[19] Nonetheless, there is considerable variability in reporting SVD of surgical aortic valves, with different definitions and inadequate long-term systematically collected core laboratory data. To guide future studies of either TAVR or SAVR valves reporting SVD and valve failure in a consistent manner, a consensus statement has been published that defines bioprosthetic valve dysfunction into four categories, i.e., SVD, non-SVD, thrombosis, and endocarditis,[20] enabling objective evaluation of durability in the same language for different studies. In the randomized NOTION trial, less severe SVD with self-expanding TAVR valves was observed than surgery (1.5% vs. 10.0%; P = 0.02), but the risk of bioprosthetic valve failure was similar (9.7% vs. 13.8%; P = 0.4) for up to 10 years.[21] In conclusion, through its two decades of development, TAVR has revolutionized the treatment pattern of symptomatic severe AS and set a blueprint for other transcatheter valve therapies. The journey starts with the aim of addressing unmet clinical needs and continues to progress in a patient-centered fashion. With the joint effort of the Heart Team and the industry partners, the field of structural heart disease has the potential for new rounds of breakthroughs. Funding This work was supported by the National Natural Science Foundation of China (Nos. 82102129 and 82170375), Technological innovation project of Chengdu Science & Technology Bureau (No. 2022-YF05-01565-SN), Chinese Medical Association Cardiovascular Branch (CSC) Clinical Research Special Fund Project (No. CSCF2020B04), and West China Hospital “1·3·5” Discipline of Excellence Project—“Mechanisms of aortic stenosis and the clinical applications”. Conflicts of interest None.