Requiem for Routine Self-Expanding TAVR Valves? A Commentary on the Comparative Analysis of Evolut PRO Versus Sapien Ultra Valves for Transfemoral Transcatheter Aortic Valve Implantation Registry (OPERA-TAVI)

Abstract

Transcatheter aortic valve replacement (TAVR) has become a valuable clinical option over the past decade for patients with severe symptomatic aortic stenosis across the range of surgical risk profiles. 1Otto CM Nishimura RA Bonow RO et al.2020 ACC/AHA guideline for the management of patients with valvular heart disease: Executive summary: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.Circulation. 2021; 143: e35-e71PubMed Google Scholar Current US Food and Drug Administration-approved TAVR device options include both balloon-expanding (BE) and self-expanding (SE) transcatheter heart valve (THV) systems, and technologic advancements with each device generation have led to rapid improvements in both short- and long-term patient outcomes. These advancements and iterative changes to procedural details, in addition to limited randomized studies, have led to difficulty in the direct comparison of BE and SE THVs with each new generation. Published in 2014, the Comparison of Transcatheter Heart Valves in High Risk Patients with Severe Aortic Stenosis trial randomized high-risk patients between the BE Sapien XT (Edwards Lifesciences, Irvine, CA) and the first-generation SE CoreValve (Medtronic, Inc, Minneapolis, MN) THVs.2Abdel-Wahab M Landt M Neumann F-J et al.5-year outcomes after TAVR with balloon-expandable versus self-expanding valves: Results from the CHOICE randomized clinical trial.JACC Cardiovasc Interv. 2020; 13: 1071-1082Crossref PubMed Scopus (89) Google Scholar,3Abdel-Wahab M Mehilli J Freker C et al.Comparison of balloon-expandable vs self-expandable valves in patients undergoing transcatheter aortic valve replacement: The CHOICE randomized clinical trial.JAMA. 2014; 311: 1503-1514Crossref PubMed Scopus (527) Google Scholar Within these older generation THVs, the BE system showed better device success compared to the SE system (95.9% v 77.5%, relative risk, 1.24; 95% CI, 1.12-1.37; p < 0.001), as well a significant reduction in the need for permanent pacemaker implant at 30 days (17.3% v 37.6%, relative risk, 0.46; 95% CI, 0.28-0.74). Importantly, however, the 30-day and 5-year safety profiles were comparable between the 2 platforms.2Abdel-Wahab M Landt M Neumann F-J et al.5-year outcomes after TAVR with balloon-expandable versus self-expanding valves: Results from the CHOICE randomized clinical trial.JACC Cardiovasc Interv. 2020; 13: 1071-1082Crossref PubMed Scopus (89) Google Scholar,3Abdel-Wahab M Mehilli J Freker C et al.Comparison of balloon-expandable vs self-expandable valves in patients undergoing transcatheter aortic valve replacement: The CHOICE randomized clinical trial.JAMA. 2014; 311: 1503-1514Crossref PubMed Scopus (527) Google Scholar Subsequently, published in 2020 and evaluating patients between 2016 and 2018, the SOLVE-TAVI trial similarly reported randomized data comparing BE and SE THV systems, this time in intermediate- to high-risk patients using the SAPIEN 3 BE-THV (Edwards Lifesciences) and the Evolut-R SE-THV (Medtronic). The 30-day composite endpoint of all-cause mortality, stroke, moderate and/or severe prosthetic valve regurgitation, and permanent pacemaker implantation was similar between the 2 groups—26.1% in the BE-THV and 28.4% in the SE-THV group.4Thiele H Kurz T Feistritzer H-J et al.Comparison of newer generation self-expandable vs. balloon-expandable valves in transcatheter aortic valve implantation: The randomized SOLVE-TAVI trial.Eur Heart J. 2020; 41: 1890-1899Crossref PubMed Scopus (120) Google Scholar Though stroke rates did not rise to statistical significance in superiority testing, a relatively large absolute difference was observed (SE 0.5%, BE 4.7%, p = 0.003). There is currently no randomized clinical trial directly comparing the most recent generation of commercially available BE-THVs (SAPIEN 3 Ultra; Edwards Lifesciences) and SE-THVs (Evolut PRO/PRO+; Medtronic, Inc). The recently published Comparative Analysis of Evolut PRO versus Sapien Ultra Valves for Transfemoral Transcatheter Aortic Valve Implantation (OPERA-TAVI) registry is an international registry from 14 high-volume TAVR centers, including 13 European centers and 1 United States center, aiming to provide some clarity on this topic.5Costa G Saia F Pilgrim T et al.Transcatheter aortic valve replacement with the latest-iteration self-expanding or balloon-expandable valves: The multicenter OPERA-TAVI registry.JACC Cardiovasc Interv. 2022; 15: 2398-2407Crossref PubMed Scopus (6) Google Scholar Employing a retrospective, propensity-matched design, OPERA-TAVI compared outcomes among 2,241 patients receiving the latest generation BE-THV (n = 912 [40.7]) and SE-THV (n = 1,329 [59.3%]) systems. Consistent with most prior work, OPERA-TAVI found no difference in the primary efficacy outcome of device success (BE 85.9% v SE 87.4%; p = 0.47), although lower mean transvalvular gradients were observed in the SE cohort (BE 12 mmHg, SE 7 mmHg; p < 0.01). However, the primary early safety outcome, defined according to the Valve Academic Research Consortium 3 definitions,6Généreux P Piazza N et al.VARC-4 WRITING COMMITTEEValve Academic Research Consortium 3: Updated endpoint definitions for aortic valve clinical research.J Am Coll Cardiol. 2021; 77: 2717-2746Crossref PubMed Scopus (160) Google Scholar significantly favored the BE THV system (82.6% BE v 69.1% SE p < 0.01). Although the secondary outcomes of all-cause death, nondisabling stroke, myocardial infarction, and heart failure rehospitalization were similar between the 2 systems, this difference in the primary safety outcome largely was driven by significant differences in disabling stroke (BE 0.7%, SE 2.3%, p = 0.03) and in permanent pacemaker implant rates (BE 10.1%, SE 17.9%; p < 0.01). This difference in stroke was in contrast to those results suggested by the SOLVE-TAVI data. The SE THV procedures in OPERA-TAVI required significantly more predilations and postdilations that partially could explain the higher rates of disabling stroke and pacemaker implant observed in the SE cohort. Importantly, OPERA-TAVI incorporated 5 prespecified anatomic subgroups that highlighted key characteristics that likely have been a source of selection bias in prior BE and SE THV comparison studies. These subgroups included the following: (1) patients with small aortic annuli, (2) moderate-to-severe aortic leaflet calcifications, (3) moderate-to-severe left ventricular outflow tract calcifications, (4) horizontal aortas, and (5) bicuspid aortic valves. They showed consistency in the primary efficacy outcomes between the BE-THV and SE-THVs across all 5 groups (all with Pinteraction > 0.10). There was significant interaction in propensity matching for the primary safety outcome in the horizontal aorta, left ventricular outflow tract calcification, and leaflet calcification subgroups (Pinteraction 0.07, 0.04, and 0.03, respectively). However, there was no significant interaction in the small annuli or bicuspid valve subgroups. Interestingly, the early safety outcome favoring BE THVs was preserved in the small-annuli group (BE 84.6 v SE 68.7%, p < 0.01), though early safety was similar between the study groups in those with bicuspid aortic valve (BE 79.6% v SE 75.5%, p = 0.64). Though propensity-score matching (PSM) is often considered the best alternative to randomization, even with meticulous application, it remains impossible to completely eliminate selection bias in observational data. This is a particularly important consideration for OPERA-TAVI, as outcome data from earlier studies like the Comparison of Transcatheter Heart Valves in High Risk Patients with Severe Aortic Stenosis and SOLVE-TAVI were very likely to have biased clinicians to use BE versus SE valves for different populations with different perceived risk profiles, such as those highlighted in the 5 prespecified subgroups of OPERA-TAVI. Early studies demonstrated higher pacemaker implantation rates for SE-THVs, which may have swayed some clinicians to avoid SE-THVs in patients viewed as “higher risk” for a pacemaker. Unfortunately, preprocedural pacemaker risk is not reliably captured or reported in demographic data, and was not used for PSM in OPERA-TAVI. Additionally, the study period included the adoption of the cusp-overlap technique, which has been shown to reduce the need for a permanent pacemaker in SE-THV patients,7Tang GHL Zaid S Michev I et al.Cusp-Overlap" view simplifies fluoroscopy-guided implantation of self-expanding valve in transcatheter aortic valve replacement.JACC Cardiovasc Interv. 2018; 11: 1663-1665Crossref PubMed Scopus (79) Google Scholar and the use of this technique was not specifically included in the analysis. Similar to prior studies on post-TAVR echocardiography, OPERA-TAVI showed lower mean gradients with SE THVs when compared to BE THVs,2Abdel-Wahab M Landt M Neumann F-J et al.5-year outcomes after TAVR with balloon-expandable versus self-expanding valves: Results from the CHOICE randomized clinical trial.JACC Cardiovasc Interv. 2020; 13: 1071-1082Crossref PubMed Scopus (89) Google Scholar, 3Abdel-Wahab M Mehilli J Freker C et al.Comparison of balloon-expandable vs self-expandable valves in patients undergoing transcatheter aortic valve replacement: The CHOICE randomized clinical trial.JAMA. 2014; 311: 1503-1514Crossref PubMed Scopus (527) Google Scholar, 4Thiele H Kurz T Feistritzer H-J et al.Comparison of newer generation self-expandable vs. balloon-expandable valves in transcatheter aortic valve implantation: The randomized SOLVE-TAVI trial.Eur Heart J. 2020; 41: 1890-1899Crossref PubMed Scopus (120) Google Scholar though with higher rates of any degree of paravalvular leak (42.7% SE v 22.5% BE, p < 0.01). Moderate-to-severe paravalvular leak across the 2 platforms was similar, however, with 3.2% in SE THVs v 2.3% in BE-THVs (p = 0.41.) Though, over time, there have been reductions in the rate and severity of paravalvular leak seen in TAVR due to changes in sealing skirt designs in both device platforms; direct comparisons to earlier generation for the routine use of intraoperative TEE for early-generation assessment versus routine TTE in newer generations often confounds TAVR valves.8Capdeville M Alfirevic A. Are transthoracic and transesophageal echocardiography equal “PARTNERS” in the assessment of paravalvular leak after TAVR?.J Cardiothorac Vasc Anesth. 2017; 31: 1285-1289Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Different medical centers and structural operators likely have different expertise and experience with the individual THV systems. As a result, they very likely have individualized criteria for choosing a particular THV that demographic data and PSM cannot completely capture. Among the 15 medical centers in OPERA-TAVI, before PSM, more Evolut PRO/PRO+ (1,329) valves were placed compared with Sapien 3 Ultra (912), suggesting that these baseline differences are indeed present. Preferences and practice patterns of individual medical centers are nearly impossible to eliminate with PSM; therefore, the data from PSM trials must be viewed with a healthy degree of skepticism. Unfortunately, the medical centers performing each procedure were not considered in the PSM. Without more detailed information, it is conceivable that this trial may not have been comparing patients receiving SE or BE THVs, but rather different medical centers that predominantly use one device platform or another. This is an important consideration, as prior studies have highlighted the effects of procedural volumes and an individual center's experience with THV systems on TAVR patient outcomes.9Vemulapalli S Carroll JD Mack MJ et al.Procedural volume and outcomes for transcatheter aortic-valve replacement.N Engl J Med. 2019; 380: 2541-2550Crossref PubMed Scopus (204) Google Scholar,10Cormican D Jayaraman A Villablanca P et al.TAVR procedural volumes and patient outcomes: Analysis of recent data.J Cardiothorac Vasc Anesth. 2020; 34: 545-550Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar In particular, with SE THV systems, institutional experience at a SE-predominant center has shown a further reduction in periprocedural risks such as cerebrovascular accident and 2-year mortality compared to SE THV use at BE THV-predominant centers.11Witberg G Landes U Talmor-Barkan Y et al.Center valve preference and outcomes of transcatheter aortic valve replacement: Insights from the AMTRAC Registry.JACC Cardiovasc Interv. 2022; 15: 1266-1274Crossref PubMed Scopus (4) Google Scholar Further, it should be noted that the generalizability of these findings may be somewhat limited for clinicians in the United States, as data used in OPERA-TAVI were drawn overwhelmingly from European medical centers. This comes with confounders related to preoperative and perioperative care models, as well as the aforementioned predominance of the SE THV system, which is in contrast to the predominance of BE THV systems in the United States.12Carroll JD Mack MJ Vemulapalli S et al.STS-ACC TVT registry oftranscatheter aortic valve replacement.Ann Thorac Surg. 2021; 111: 701-722Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Transcatheter aortic valve replacement has rapidly expanded over the past decade as a treatment option for patients with severe symptomatic aortic stenosis, surpassing that of isolated surgical aortic valve replacement in the United States in 2019.12Carroll JD Mack MJ Vemulapalli S et al.STS-ACC TVT registry oftranscatheter aortic valve replacement.Ann Thorac Surg. 2021; 111: 701-722Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar With this expansion is a rapidly growing experience and understanding of patient and device factors that influence meaningful patient-centered outcomes, though direct randomized data to guide ideal device selection have tended to lag behind each iterative THV generation. The OPERA-TAVI registry data have offered real-world insights into current device outcomes with the most recent generation of BE and SE THV systems, with similar technical success rates across these devices. The decreased early safety in even the newest generation of SE-THV systems compared to BE-THV systems is driven by an increased need for permanent pacemaker insertion and higher stroke rates. The choice of an SE versus BE THV for a particular patient at a smaller or less-experienced medical center may require a more pragmatic approach. The structural heart team, including interventional cardiologists, anesthesiologists, and cardiac surgeons, must consider what services and expertise are immediately available and tailor their approach with this in mind. Though the current generation BE and SE THV systems have relatively comparable composite endpoints, these devices are not identical from a vascular access or deployment standpoint. The immediate availability of particular subspecialty services, including vascular surgery, should be a consideration in certain populations. Although prior work did not demonstrate clear differences in major vascular complications between BE and SE valves,13Van Belle E Vincent F Labreuche J et al.Balloon-expandable versus self-expanding transcatheter aortic valve replacement.Circulation. 2020; 141: 243-259Crossref PubMed Scopus (88) Google Scholar OPERA-TAVI did demonstrate higher major vascular complications in SE THVs (SE 5.4% v BE 1.9%, p < 0.01).5Costa G Saia F Pilgrim T et al.Transcatheter aortic valve replacement with the latest-iteration self-expanding or balloon-expandable valves: The multicenter OPERA-TAVI registry.JACC Cardiovasc Interv. 2022; 15: 2398-2407Crossref PubMed Scopus (6) Google Scholar Retrospective studies on this topic were likely affected by significant selection bias, as iliofemoral anatomy may influence the choice of an inline femoral sheath or peripheral vascular intervention before TAVR sheath placement. Though the authors of OPERA-TAVI detailed key cardiac anatomic differences between their populations, this study did not evaluate or capture details of the femoral anatomy and periprocedural vascular interventions. With the higher rates of disabling stroke and pacemaker implantation despite similar device success, is OPERA-TAVI the requiem for routine SE valve implantation? In short, probably not. Though these data suggested meaningful real-world differences between SE and BE THV systems that should give structural heart disease teams pause, it would be premature to draw definitive conclusions from this propensity-matched analysis. Careful preprocedural analysis, coordination of medical center experience, and consideration of individual patient factors are still important components in orchestrating a successful TAVR program and improved patient outcomes. As the latest generation Sapien X4 BE-THV (Edwards Lifesciences) and Evolut FX SE-THV (Medtronic) systems emerge, the authors look forward to future studies and randomized controlled trials to drive clinicians toward the final coda in optimized device selection. None.