Midterm outcomes of aortic valve replacement using a rapid-deployment valve for aortic stenosis: TRANSFORM trial

Background The use of rapid-deployment valves (RDVs) has been shown to reduce the operative time for surgical aortic valve replacement (AVR). Long-term core laboratory–adjudicated data are scarce, however. Here we report final 7-year data on RDV use. Methods TRANSFORM was a prospective, nonrandomized, multicenter, single-arm trial implanting a stented bovine pericardial valve with an incorporated balloon-expandable sealing frame. A prior published 1-year analysis included 839 patients from 29 centers. An additional 46 patients were enrolled and implanted, for a total of 885 patients. Annual clinical and core laboratory–adjudicated echocardiographic outcomes were collected through 8 years. Primary endpoints were structural valve deterioration (SVD), all-cause reintervention, all-cause valve explantation, and all-cause mortality. Secondary endpoints included hemodynamic performance assessed by echocardiography. The mean duration of follow-up was 5.0 ± 2.0 years. Results The mean patient age was 73.3 ± 8.2 years. Isolated AVR was performed in 62.1% of the patients, and AVR with concomitant procedures was performed in 37.9%. Freedom from all-cause mortality at 7 years was 76.0% for isolated AVR and 68.2% for concomitant AVR. Freedom from SVD, all-cause reintervention, and valve explantation at 7 years was 97.5%, 95.7%, and 97.8%, respectively. The mean gradient and effective orifice area at 7 years were 11.1 ± 5.3 mm Hg and 1.6 ± 0.3 cm2, respectively. Paravalvular leak at 7 years was none/trace in 88.6% and mild in 11.4%. In patients undergoing isolated AVR, the cumulative probability of pacemaker implantation was 13.9% at 30 days, 15.5% at 1 year, and 21.8% at 7 years. Conclusions AVR for aortic stenosis using an RDV is associated with low rates of late adverse events. This surgical pericardial tissue platform provides excellent and stable hemodynamic performance through 7 years.


Overall
Freedom from all-cause reintervention at 7 years after rapid-deployment valve implantation.

CENTRAL MESSAGE
The INTUITY rapid-deployment valve provides excellent and stable hemodynamic results through 7 years, with a low rate of late adverse events.

PERSPECTIVE
The use of bioprosthetic valves in aortic valve replacement demands scrutiny of durability over time.This multicenter clinical trial with core laboratory-adjudicated echocardiography followed 885 subjects receiving a rapiddeployment valve through 7 years, demonstrating restoration of survival to an age-matched cohort and durability comparable to contemporary surgical and transcatheter bioprosthetic valves.
Surgical aortic valve replacement (AVR) historically has been the standard for the treatment of patients with aortic stenosis.As techniques and technology have evolved, minimally invasive AVR has become an acceptable modality without an increased risk of major complications or death while offering faster recovery time, reduced blood loss, and shorter hospital length of stay. 1 However, longer cross-clamp and bypass times associated with minimally invasive AVR have hindered its widespread use.Yet advancements in bioprosthetic valve design and the subsequent development of rapid-deployment valves (RDVs) has now changed this narrative.The use of RDVs has been shown to reduce operative times for surgical aortic valve replacement and facilitate minimally invasive approaches. 2,36][7] AVR operations with concomitant procedures are within the domain of surgical AVR and technology to shorten cross-clamp times is tantamount in  TRANSFORM was a medical investigational device study run under the authority of the US Food and Drug Administration (ClinicalTrials.govNCT01700439).The purpose of the study was to assess the safety and effectiveness of the Edwards INTUITY Elite valve system (Edwards Lifesciences) in patients with aortic stenosis or stenosisinsufficiency necessitating primary replacement of the native aortic valve.This prospective, clinical, and core laboratory-adjudicated echocardiographic study evaluated a bioprosthetic valve surgically implanted with a rapid deployment technique with and without a minimally invasive approach. 8,9Here we present the final 7-year outcome of the INTUITY Elite valve system.

METHODS
The Edwards INTUITY Elite valve system is a rapid-deployment pericardial trileaflet stented aortic bioprosthesis.This design combines the technology of the Edwards Perimount Magna Ease (Edwards Lifesciences) bovine pericardial valve and a subannular balloon-expandable stainless steel cloth-covered frame that is deployed in the left ventricular outflow tract.A cloth skirt covers the balloon-expandable stainless steel inflow frame, providing a firm seal between the aortic annulus and the expanded frame.A prospective nonrandomized multicenter single-arm trial-TRANSFORM (Multicenter Experience with Rapid Deployment Edwards INTUITY Valve System for Aortic Valve Replacement; ClinicalTrials.govNCT01700439)-was conducted to evaluate the performance of the aortic RDV in patients with severe aortic stenosis.The published 1-year analysis included 839 patients from 29 centers who underwent either isolated AVR or AVR with concomitant cardiac procedures. 3An additional 46 patients were enrolled and implanted, for a total of 885 patients from 2012 to 2016; these patients are the subject of this report.
Study results were adjudicated by both annual clinical and core laboratory echocardiographic data through 8 years.Clinical endpoints as specified by Akins and colleagues' definitions were adverse events, including all-cause mortality, structural valve deterioration (SVD), all-cause reintervention, and all-cause explantation. 10Of note, reintervention also encompassed all percutaneous interventional catheter procedures.Hemodynamic performance was assessed by echocardiography.These endpoints are the basis for this report and are summarized in a graphical abstract (Figure 1).The mean duration of follow-up was 5.0 years.Follow-up compliance at 5 years was 90.7% of eligible patients for the visit, and 81.2% had a core laboratory echocardiographic evaluation.Survival of an age-and sex-matched cohort was constructed from the 2016 period life table for the Social Security population. 11 E1.

Statistical Analysis
The sites were responsible for accurate data collection.Descriptive data including patient baseline characteristics and hemodynamic performance at baseline, 1 year, 5 years, and 7 years were summarized by mean with standard deviation for continuous variables and by frequency with percentage for categorical variables.Rates of freedom from SVD, all-cause reintervention, all-cause valve explantation, and all-cause mortality with 95% confidence intervals were estimated using Kaplan-Meier methods.All statistical analyses were performed using R version 4.2.3 (R Core Team) and SAS version 9.4 (SAS Institute).

RESULTS
Figure 2 outlines the follow-up for the 885 implanted patients, and Table 1 presents their baseline demographics and operative variables.The mean patient age was 73.3 AE 8.2 years.Isolated AVR was performed in 62.1%, and AVR with concomitant procedures was performed in 37.9%.Table 2 outlines the perioperative 30-day outcomes as reported previously. 3Freedom from all-cause mortality at 7 years was 76.0% for isolated AVR and 68.2% for concomitant AVR (Figure 3, A).An age-and sex-matched cohort from the US general population had a predicted survival at 7 years of 72.3%.Freedom from SVD, allcause reintervention, and all-cause explantation at 7 years were 97.5%, 95.7%, and 97.8%, respectively (Figure 3, B-D).A total of 13 explantations were performed in 7 years, in including 5 due to aortic regurgitation, 6 due to SVD, and 2 due to endocarditis.In addition, low rates of safety events were observed through 7 years, with rates of freedom from thromboembolism, major bleeding, valve thrombosis, and endocarditis of 85.2%, 87.2%, 99.6%, and 99.2%, respectively (Figure E1).Mean gradient and effective orifice area were 9.9 AE 5.5 mm Hg and 1.7 AE 0.3 cm 2 , respectively, at 5 years and 11.1 AE 5.3 mm Hg and 1.6 AE 0.3 cm 2 at 7 years (Table 3, Figure 4).The degree of paravalvular leak (PVL) at 7 years was none/trace in 88.6% and mild in 11.4%.In the subset of patients undergoing isolated AVR, the cumulative probability of pacemaker implantation was 13.9% at 30 days, 15.5% at 1 year, and 21.8% at 7 years.Furthermore, the 7-year cumulative probability of pacemaker implantation for complete heart block was 10.9%.

DISCUSSION
The TRANSFORM trial is one of the largest US Investigational Device Exemption trials of a contemporary bioprosthetic valve.A previous study of 1-year results using this class of bioprosthetic valves demonstrated both safety and efficacy. 3This current analysis based on 885 patients found rates of overall survival, freedom from SVD, and freedom from all-cause reintervention at 7 years of 73.2%, 97.5%, and 95.7%, respectively.No patients had moderate or greater PVL, and the mean gradient was 11.1 mm Hg at 7 years.Previously noted pacemaker implantation rates 12 were stable, at a cumulative rate of 21.8% for isolated AVR at 7 years.Additionally, 7-year overall survival after AVR with the INTUITY valve was similar to that in an age-and sex-matched US population (73.2% vs 72.3%) (Figure 5).
Although our results are early, the data reinforce the previously reported 8-year outcomes for the Magna Ease valve, which offers promise for continued durability. 13Leaflet treatment aims to reduce the calcification of free aldehydes that results from the fixation process of biological tissue.The proprietary process is unique to each manufacturer; in this particular valve, the ThermoFix process was used for all implanted INTUITY valves.As such, acceptable gradients are stable after 7 years and compare favorably with earlier generations of this bioprosthetic valve (Table 2, Figure 3, B).
Although no patients had moderate or greater PVL, the rate of mild PVL was 11.4% at 7 years.In comparison, the rates of mild PVL associated with other surgical valves include 1.6% at 8 years for Magna Ease 13 and 0.9% at 5 years for Avalus. 6Additionally, moderate-severe PVL at 5 years for current generation of transcatheter heart valves is 21.6% (Notion trial). 14The importance of mild PVL as a marker for the future progression of leak, risk of  For transcatheter AVR patients, even mild paravalvular insufficiency at 1 month postprocedure has been identified as a marker for increased 5-year mortality. 15,16garding permanent pacemaker implantation (PPI), Romano and colleagues 12 reported an all-cause PPI rate of 12.3% at discharge and 15.1% at 1 year after AVR in all patients.The all-cause PPI rate in patients without baseline conduction abnormalities was 6.6% at discharge  17,18 A follow-up study revealed only a single new PPI in 87 patients at risk over the 2 years of monitoring, for a cumulative rate of 10.1%. 18This is in alignment with the reported 2year cumulative PPI rates of 9.1% for transcatheter AVR and 7.0% for surgical AVR in the PARTNER 3 study. 19

Limitations
There are limitations to this study.First, the trial was single-armed, and thus no comparative effectiveness analysis could be done with control valves that were available at the time of trial enrollment.Second, rehospitalization rate was not a secondary endpoint.At the time of trial design, valve endpoints were guided by the Akins guidelines, as Valve Academic Research Consortium endpoints were not available.We supplemented for this by including transcatheter aortic valve-in-valve or PVL closure as reinterventions.Finally, no further follow-up is planned in the TRANSFORM trial.

CONCLUSIONS
AVR for aortic stenosis using a RDV is associated with a low rate of late adverse events.Our analysis of 7-year follow-up data from the TRANSFORM prospective nonrandomized multicenter single-arm trial using the Edwards INTUITY Elite valve system shows that the valve system has consistently demonstrated sustained and comparable clinical and hemodynamic outcomes.This dataset provides a contemporary baseline performance benchmark for surgical AVR for aortic stenosis.

Conflict of Interest Statement
Dr Malaisrie reported research grants, consulting fees, and honoraria from Edwards Lifesciences, Medtronic, Artivion, and Terumo Aortic.Dr Mumtaz reported consulting fees, honoraria, and research grants from Edwards Lifesciences, Medtronic, AtriCure, Teleflex, and Abbott.Dr Barnhart  Ryan, Patel, Woo, and Dorsey reported no conflicts of interest.
The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest.The editors and reviewers of this article have no conflicts of interest.

Methods:
TRANSFORM is a prospective, nonrandomized, multicenter, single-arm trial implanting a stented bovine pericardiaI valve with an incorporated balloon-expandable sealing frame.In this study, 885 patients received the INTUITY valve across 29 sites.Endpoints include adverse clinical events and core-lab adjudicated echocardiographic data.Results: Mean patient age was 73.3 ± 8.2 years.Freedom from all-cause reintervention for isolated and concomitant AVR were 95.5% and 96.1% at 7 years, respectively.Clinically stable echocardiographic hemodynamic parameters through 7 years.Implications: This surgical pericardial tissue platform provides excellent and stable hemodynamic performance through seven years.Aortic valve replacement for aortic stenosis using a rapiddeployment valve is associated with low rate of late adverse events.Midterm outcomes of aortic valve replacement using rapid-deployment valve for aortic stenosis: TRANSFORM was conducted using Good Clinical Practices in accordance with 21 CFR Part 812 (Investigational Device Exemption), 21 CFR Part 50 (Protection of Human Subjects), CFR Part 54 (Financial Disclosure by Clinical Investigators), 21 CFR Part 56 (Institutional Review Boards), and the Health and Insurance Portability and Accountability Act.The clinical protocol, consent form, and protocol amendments were approved by an Institutional Review Board at each investigational site, as detailed in Table

after Implant Freedom from All Cause Reintervention (%)
FIGURE 1. Graphical abstract.Results demonstrating echocardiographic hemodynamic performance and freedom from all-cause reintervention over 7 years.EOA, Effective orifice area; AVR, aortic valve replacement.

TABLE 1 .
Baseline characteristics and operative variables of implanted subjects (N ¼ 885) SD, Standard deviation; NYHA, New York Heart Association; STS, Society of Thoracic Surgeons; AVR, aortic valve replacement; CABG, coronary artery bypass grafting; MIS, minimally invasive surgery.

TABLE 2
endocarditis, and hemolysis has been debated but has not been borne out in this study.
reported consulting for Articure and Artivion.Dr Chitwood reported consulting for NeoChord and Edwards Lifesciences.Dr Accola reported consulting fees and honoraria from Edwards Lifesciences.Dr Dewey reported serving as a speaker for Abbott as well as a speaker, proctor, and consultant for Edwards Lifesciences.Dr Koulogiannis reported consulting for Edwards Lifesciences and Abbott.Dr Grossi reported intellectual property and royalties from Medtronic for valve repair devices and intellectual property and royalties from Edwards Lifesciences.Drs Echocardiographic hemodynamic performance over time.EOA, Effective orifice area.
FIGURE 5. Freedom from all-cause mortality comparing the TRANS-FORM cohort (blue line) and the age/sex-matched SSA cohort (green line).SSA.Social Security Administration.