Mid-term outcomes of the COMMENCE trial investigating mitral valve replacement using a bioprosthesis with a novel tissue

Objective Novel tissue leaflets (RESILIA tissue) may improve durability of bioprosthetic heart valves. The COMMENCE trial is an ongoing prospective study to evaluate valve replacement using RESILIA tissue. This report describes mid-term outcomes in the mitral cohort of COMMENCE. Methods Adult patients requiring mitral valve replacement were enrolled in a prospective, single-arm trial at 17 sites in the United States and Canada. An independent clinical events committee adjudicated safety events using definitions from established guidelines, and hemodynamic performance was evaluated by an independent echocardiographic core laboratory. Results Eighty-two patients (median age 70 years) successfully underwent mitral valve replacement with the study valve. Five-year event-free probabilities for all-cause mortality, structural valve deterioration, and reoperation were 79.9%, 98.7%, and 97.1%, respectively. Hemodynamic valve function measurements were stable through the 5-year follow-up period; valvular leaks were infrequently observed and primarily clinically insignificant/mild. Conclusions Mitral valve replacement patients implanted with a RESILIA tissue bioprosthesis had a good safety profile and clinically stable hemodynamic performance.


Event-Free Probability
Freedom from death and structural valve deterioration at 5 yrs. in COMMENCE mitral patients.

CENTRAL MESSAGE
Through 5 years of patient followup, mitral valve replacement patients implanted with a RESILIA tissue bioprosthesis had a good safety profile and clinically stable hemodynamic performance.

PERSPECTIVE
Patient preferences in mitral valve replacement are evolving, as the use of anticoagulation falls out of favor; meanwhile, reoperations have become safer with catheter-based valve-in-valve replacements a reality.Improved durability is the focus of new tissue valve designs.This study reports outcomes of a new pericardial tissue designed to reduce leaflet calcification and improve long-term durability.
Mitral valve disease is one of the most common valvular heart diseases, with functional classifications of mitral regurgitation together affecting an estimated 5% of the US population and resulting in approximately 29,000 hospitalizations in the United States in 2018. 1 Further, prevalence is increasing in developed nations as the population ages. 2 Current valvular heart disease guidelines establish that mitral valve replacement (MVR) may be considered in patients with mitral regurgitation and mitral stenosis when durable repair is not feasible. 34][5] Patients can be implanted with either a bioprosthetic valve or a mechanical valve.Mechanical valves may offer longer durability but require lifelong anticoagulation with a potential risk of bleeding or pannus formation with leaflet restriction depending on the adequacy of anticoagulation. 6In contrast, bioprosthetic valves have been associated with greater risk of structural valve deterioration (SVD), especially in younger patients, and with reduced overall survival in patients younger than 50 years. 7,8The potential of valve-in-valve therapies may reduce the need for redo MVR, thereby impacting the likelihood of younger patients receiving a bioprosthetic valve.Taken together, balancing patient quality of life and the competing risks of reoperation and potential bleeding events requires long-term data to inform decision-making on appropriate valve selection. 9ESILIA tissue designed for use in heart valve replacement is a promising option that may improve durability of bioprosthetic valves.The tissue incorporates a novel integrity preservation technology, which prevents calcium binding through stable capping of residual aldehyde groups and allows dry tissue storage via glycerolization.RESILIA tissue has exhibited reduced tissue calcification in preclinical studies compared with both previous bovine tissue preparations and porcine tissues treated with amino oleic acid. 10hen evaluated in a juvenile sheep model, RESILIA tissue To view the AATS Annual Meeting Webcast, see the URL next to the webcast thumbnail.
valves implanted in the mitral position exhibited reduced transvalvular pressure gradients and approximately 72% less calcium relative to the PERIMOUNT control group after 8 months. 11linically, the European Aortic Feasibility Study investigated RESILIA tissue in aortic valve replacement with a good hemodynamics profile and no SVD observed through 5 years of follow up. 12The COMMENCE Investigational Device Exemption trial was planned to evaluate performance of RESILIA tissue in both aortic and mitral valve replacement.Promising outcomes have been observed through 5 years of follow-up in the aortic position with clinically stable hemodynamics and no evidence of SVD reported. 13Herein, we report mid-term outcomes of the mitral cohort of the COMMENCE trial.The objective of this study was to evaluate safety and effectiveness of mitral valve replacement with RESILIA tissue.

METHODS
The COMMENCE trial was designed as a prospective, single-arm Food and Drug Administration Investigational Device Exemption trial with enrollment of the mitral cohort at 17 sites in the United States and Canada.Patients underwent MVR with Model 11000M (Edwards Lifesciences LLC), a pericardial mitral bioprosthesis with RESILIA tissue.This trileaflet bioprosthesis is the same as the Carpentier-Edwards PERIMOUNT Magna Mitral Ease valve (Model 7300TFX; Edwards Lifesciences), except including RESILIA tissue leaflets.
Patients older than 18 years old with mitral valve disease requiring replacement based on a preoperative evaluation and scheduled to undergo MVR with or without coronary artery bypass graft were eligible.Concomitant tricuspid valve repair and the maze procedure were allowed; no other valve replacements were allowed as part of the procedure.Patients with acute myocardial infarction within 30 days before surgery, cerebrovascular accident within 6 months, ejection fraction less than 20%, or renal failure, or who required emergency surgery, were not eligible for inclusion in the study.The decision for antiplatelet or anti-coagulation (AC) therapy was not dictated per protocol but rather left to the physician's discretion per existing American College of Cardiology/American Heart Association guidelines for the management of patients with valvular heart disease. 3The institutional review board of each participating site approved the study protocol and publication of data.Institutional review board approval details for each center are listed in Table E1.Written informed consent, in accordance with applicable international standards and trial center regulations, was obtained from each study participant, before enrollment and any trial procedures.The patient(s) provided informed written consent for the publication of the study data.
End points were defined in consultation with the US Food and Drug Administration.An independent Clinical Events Committee adjudicated end point-related adverse events, using definitions from the established guidelines at the time of study development. 14Safety end points included all-cause mortality, reoperation, valve explant, thromboembolism, valve thrombosis, endocarditis, all bleeding, major paravalvular leak, hemolysis, SVD, and nonstructural valve dysfunction (NSVD).As detailed by Akins and colleagues, 14 SVD was defined as dysfunction or deterioration involving the operated valve (exclusive of infection or thrombosis), as determined by reoperation, autopsy, or clinical investigation.Conversely, NSVD was defined as any abnormality not intrinsic to the valve itself that results in stenosis or regurgitation of the operated valve or hemolysis. 14emodynamic performance was evaluated by an independent echocardiography core laboratory (BioTelemetry Research).Hemodynamic assessments for this analysis included peak mitral valve velocity, peak and mean mitral pressure gradients, effective orifice area (EOA), Doppler

Abbreviations and Acronyms
AC ¼ anti-coagulant DVI ¼ Doppler velocity index EOA ¼ effective orifice area MVR ¼ mitral valve replacement NSVD ¼ nonstructural valve dysfunction SVD ¼ structural valve deterioration velocity index (DVI), and severity of valve regurgitation.Paravalvular or transvalvular regurgitation were graded as none, trace, mild, moderate, and severe.Statistical analysis was performed by the study sponsor, Edwards Lifesciences, per the protocol and statistical analysis plan.Descriptive summary statistics for categorical variables are the percentage of subjects with a recorded value for variables of interest.Median (interquartile range) are presented for continuous measures after assessing for normality.Kaplan-Meier analyses were undertaken on safety end points of all patients successfully implanted with the study valve.SAS, version 9.3 (SAS Institute Inc) was used for all statistical analyses.Midterm results through a data extraction date of July 21, 2022, are reported herein.

RESULTS
Between January 2013 and February 2016, 83 patients were enrolled at 17 centers in North America, with 82 patients successfully implanted with the study valve.One patient had major paravalvular leak (4þ) after the heart was restarted before leaving the operating room and was deemed a technical failure; this patient was reintervened with a 27-mm Magna Mitral Ease valve.The median follow-up for the study cohort was 5.1 (1.4) years (total 374.2 patient-years in aggregate).There were 15 deaths (2 valve-related), 1 explant (due to NSVD), 1 reintervention (due to SVD), 6 who withdrew consent, 3 who were exited due to being lost to follow-up, and 3 who missed the 5-year visit, leaving 54 patients with available data at 5-year follow up (Figure 1).
Patients were predominantly elderly and had concomitant cardiovascular conditions.Median patient age at the time of the procedure was 70 years, with 52.4% of patients 70 year old and older (Table 1).The median Society of Thoracic Surgeons predicted risk of operative mortality was 3.4% (2.7%).Of the 82 patients implanted with the trial valve, the following diagnoses were present in the cohort: 48.8% pure insufficiency (n ¼ 40/82), 30.5% stenosis with insufficiency (n ¼ 25/82), 11.0% stenosis (n ¼ 9/82), 7.3% prosthetic valve dysfunction (n ¼ 6/82), and 2.4% other diagnosis (n ¼ 2/82).A majority of patients were taking antiplatelet therapy (51.2%), and 46.3% of patients were taking anticoagulant therapy at baseline.Fewer than half of the patients (42.7%) underwent an isolated MVR.A similar number underwent MVR with concomitant procedures, including atrial ablation or left atrial appendage ligation.Of note, nearly 15% of the cohort underwent coronary artery bypass graft along with the valve procedure.
Adverse events in the postoperative period are summarized in Table 2. All-cause mortality within 30 days of MVR was 1.2%.There were 2 early ischemic strokes related to the procedure (2.4%) and 1 early bleeding event (1.2%) due to an esophageal tear, also deemed procedurerelated.No study valve explants, valve thrombosis, endocarditis, hemolysis, or reoperations were observed in the Five-year event-free probabilities for all-cause mortality, SVD, and reoperation were 79.9%, 98.7%, and 97.1%, respectively (Table 2).The risk of death exceeded that of SVD throughout the follow-up period, as shown in the Kaplan-Meier curve (Figure 2).Two patients underwent reoperations: 1 for NSVD and 1 for SVD.Approximately 1-year postimplant, the patient with NSVD presented with severe mitral regurgitation.The posterior leaflet was thickened and stuck in intermediate position resulting in a severe, eccentric leak.The patient was reintervened with a 29-mm Magna Mitral Ease valve (Edwards Lifesciences) shortly thereafter.Upon postexplant investigation, the valve had signs of pannus overgrowth on both leaflets with no evidence of SVD.The observed SVD occurred in a 77 year-old patient implanted with the trial valve.The patient presented with end-stage renal disease on hemodialysis and underwent valve-in-valve with a 29-mm SAPIEN 3 (Edwards Lifesciences) transcatheter heart valve on postoperative day 638 for severe central regurgitation.The second NSVD was observed in a patient who was hospitalized for chronic heart failure in the setting of severe right ventricular dysfunction.Clinically, the patient presented with mild-tomoderate stenosis seen functionally as elevated mitral valve pressure gradients, which the clinical events committee deemed as NSVD due to study valve stenosis.The patient did not require reintervention as of the 5-year follow-up visit.
A variety of valve function measurements were evaluated by echocardiography (Figure 3).Stable pressure gradients were observed from discharge to 5 years (4.1 [2.0] and 3.7 [2.2] mm Hg, respectively).Peak mitral velocity was also stable during the following up period (1.6 [0.4] m/s, discharge; 1.6 [4.0] m/s, 5 years).Effective orifice areas (EOAs) were lower than expected during the follow-up period (1.2 [0.6] cm 2 , discharge; 1.4 [0.6] cm 2 , 5 years).Given that literature suggests the continuity equation may underestimate EOAs due to variability in left ventricular outflow tract diameter measurements, DVI is presented to supplement the EOA data. 15,16From discharge to 5 years follow-up, DVI was stable (2.4 [1.3] and 2.0 [0.8], respectively) and largely within expected range.New York Heart Association class improved universally after MVR, and 94% of patients were maintained in New York Heart Association class I or II through 5 years of follow-up.In addition, clinically insignificant trivial to mild paravalvular or transvalvular leak was predominantly observed.(Figure 4).

DISCUSSION
Through 5 years of follow-up, the COMMENCE Mitral trial reported a good safety profile and clinically stable hemodynamic performance of a bioprosthetic valve with RE-SILIA tissue.These findings are consistent with the midterm safety and efficacy outcomes observed with the RESILIA tissue in the aortic position.Durability results are promising with 2 observed reoperations (1 NSVD, 1 SVD) and a reported freedom from SVD at 5 years of 98.7%.Mitral valve pressure gradients are the most common measure of valve function, whereas EOAs are more difficult to measure and may be less predictive of valve dysfunction. 17As such, DVI was also included as an additional measure to document any significant change or deterioration in valve function.Hemodynamics were clinically stable, as measured by mean valve gradients, peak velocities, DVI, and EOAs.
9][20][21] A   All events as defined by Akins and colleagues 14 and as adjudicated by Clinical Events Committee.All percentages computed as % of the total number of successfully implanted patients (N ¼ 82).One patient was omitted from further analysis due to major PVL (4þ) after the heart was restarted before leaving the operating room and was deemed a technical failure; this patient was reintervened with a 27-mm Magna Mitral Ease valve.CI, Confidence interval; SVD, structural valve deterioration; NSVD, nonstructural valve dysfunction; PVL, paravalvular leak.*Major PVL ¼ paravalvular leak of any grade requiring surgical intervention or considered a serious adverse event.
0][21] It is important to note that all of these studies represent single-center retrospective studies without clinical events committee adjudicated safety end points or core laboratory-adjudicated echo data.In addition, study cohort characteristics need to be carefully considered when comparing these results (eg, demographics, study location).Lastly, the interpretation of the Akins definition varies greatly from study to study.
3][24] As such, COMMENCE Mitral is unique in that it reports the first clinical data of RESILIA tissue in the mitral position and is a prospectively collected MVR clinical trial.Given the level of scientific rigor in this trial, the observed 98.7% freedom from SVD rate compares favorably relative to other published mid-term MVR studies.The patients in COMMENCE Mitral are demographically similar when compared with MVR populations in published literature. 8,18Surgical outcomes were excellent compared with risk scores, allowing more focus on actual valve function.The trial data set followed more standardized definitions for safety events than a retrospective single-center analysis and were adjudicated by a clinical events committee.In addition, all echocardiography results were adjudicated rigorously by an independent echo-core laboratory, and high compliance with follow-up visits was achieved (95%).Overall, the study is encouraging for durability of RESILIA tissue in the mitral position.
Although this trial presents highly relevant outcomes, it is not without limitations.This study is limited by small cohort size.20][21][22]25 As a result, long-term follow-up is needed to understand whether these findings are maintained beyond 5 years.This limitation will be addressed in part when outcomes from the 10-year COMMENCE trial extended follow-up cohort are evaluated.Further, real-world data on acute and long-term safety and performance of the MIT-RIS RESILIA Mitral valve will be collected in the prospective, global MOMENTIS trial with outcomes reported through 10 years' postimplant (https://clinicaltrials.gov/ ct2/show/NCT05526560).
The clinical implications of this study support the use of RESILIA tissue in the mitral position with excellent hemodynamics and durability out to 5 years.This is important as younger patients are requesting tissue bioprostheses and are in need of improved durability.The MITRIS RESILIA mitral valve is now available for clinical use in the United States and Japan and will contribute to further information on durability.

CONCLUSIONS
Through 5 years of follow-up, the COMMENCE Mitral trial reported a good safety profile and clinically stable  Thank you.I wanted to again congratulate Dr Heimansohn and his colleagues for presenting these data, for allowing me to review the presentation ahead of time, and we all fully agree with efforts to enhance durability of bioprosthetic valves studied here with a resilient platform.The authors demonstrated safety with excellent early mortality-it's actually 4 times better than predicted-low gradients, excellent New York Heart association class with a follow-up of 4 years.So, I'd like to make several comments and ask several questions of the authors because the study highlights the difficulty and challenges of such studies.To begin with, if we compare it with the COMMENCE aortic trial, the enrollment here was one-eighth of that, which I think has to do with the selection of patients.Most of us will repair most mitral valves for particularly and specifically this reason.The second is that the study is mostly a study of elderly patients, 80% older than 60 years and more than 50% older than 70 years.So presumably, the etiology for mitral valve replacement is significant mitral calcium and stenosis, perhaps with some element of regurgitation that cannot be repaired, and we know that those patients do not do as well long term.In addition, only two-thirds of the patients had follow-up data.A total of 13.4% died in 4 years, again highlighting the complexity of these patients, and therefore only twothirds of the patients had echocardiographic data.
Finally, the definitions used here, which are the common, standard definitions of an [inaudible], published in 2008, really underestimate the incidence of valve degeneration.And again, a publication by Dr Devere, my colleague, in 2018 in Circulation, with several of the panelists here being coauthors, demonstrated that there are morphologic valve changes that precede physiologic changes, including regurgitation of gradient before we get to the point of structural valve degeneration.So, the questions I had to the authors are-one is patient selection, one is were tricuspid valve repairs excluded, just to make a more pure patient selection?The other is anticoagulation strategy for the patients.The third in their own practice now, given these data-and it's very young data, intermediate data, which we know the majority of degeneration occurs at 8 or greater yearswould they choose porcine pericardial or mechanical valves in their patients?What is the follow-up that is required for all bioprosthetic valves, particularly in these patientstransthoracic echo, computed tomography (CT), because again as the failure that they reviewed noted were talking and focusing on valve calcification-but perhaps we should equally focus on valve thrombosis?And finally, given the very small denominator that is expected to decrease with attrition of some of these patient population, at the end of 10 years, would we have to extrapolate data from aortic valve implantation in the COMMENCE trial to mitral and tricuspid valves?I really thank the association for the opportunity to comment on this important work.
Dr David Heimansohn (Indianapolis, Ind).Thank you, Dr Aldea for taking your time to review this presentation and you asked spot-on questions, some of which have answers and some of which don't.This study absolutely was limited because of the strict patient selection.They did not allow tricuspid valve repair.And, there was a lot of discussion at the time of the study design and the ongoing study, and near the end, I believe they changed it and allowed it, but that severely limited patient enrollment.The anticoagulation was standard, 3-month anticoagulation after mitral valve repair, and then per the site's choice, depending on atrial fibrillation and other reasons to undergo anticoagulation.Your valve choice is something we all face every day, and being a busy mitral valve surgeon, as we all are on this presentation, nobody wants mechanical valves.Nobody wants to deal with warfarin.It's striking to me, even when you push patients and recommend it, they don't want it.
So, I think that's where the value of these kind of research studies are and even if you can make an incremental improvement in a valve's success and durability, I think you've gone a long way to helping this population.The other key question, follow-up-in fact, there's been a lot of discussions with this as well, and I'm involved in other valve studies where I think the science is evolving to 4dimensional CT scans, certainly in the aortic positionwhether it ends up being in the mitral position as well, time will tell.But that's certainly something that gives us more and different information than the echos do because the echos are more physiologic and flow, and the CT gives you much more anatomic details and can certainly quantitate calcification.And finally, this is going to be carried out to 10 years.Obviously-who knows-it may be single digits by the time we get to 10 years because the median age is 70 years of age.And it probably will have to be correlated with the aortic study, which they've recently decided to follow those patients younger than age 65 years as a 11year substudy, so that may help answer some of the questions, at least for the tissue processes in this complex tissue valve world.

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FIGURE 3 .
FIGURE 3. Echocardiography-derived valve hemodynamic outcomes over the follow-up period: A, Mean mitral pressure gradients; B, effective orifice area; C, Doppler velocity index (DVI); and D, peak velocity.

TABLE 1 .
Baseline patient and procedure characteristics 18R, Interquartile range; STS, Society of Thoracic Surgeons; NYHA, New York Heart Association; MVR, mitral valve replacement.*Patientsmayhave undergone more than one concomitant procedure; therefore, percentages may sum to more than 100%.yOtherproceduresincluded atrial ablation, left atrial appendage closure, maze procedure, and tricuspid valve repair.comparativeanalysis of 940 MVR patients implanted with either Medtronic Mosaic or PERIMOUNT mitral valves reported 5-year rates of echocardiographic freedom from SVD of 91.0% and 90.3%, respectively.18Further,publications for the PERIMOUNT Magna, Medtronic Mosaic, and Abbott Epic bioprosthetic valves reported Methods: Prospective, single arm trial at 17 sites in the United States and Canada, enrolling 83 patients requiring mitral valve replacement.

TABLE 2 .
Safety events Heimansohn et al Adult: Mitral Valve hemodynamic performance of a bioprosthetic valve with RESILIA tissue.Longer-term follow up is needed to fully assess durability of this novel option for mitral valve replacement.Conflict of Interest Statement E.R. reported research/consulting fees from Abbott, Edwards Lifesciences, Boston Scientific, and AtriCure.H.T. reported consultant, Edwards Lifesciences.F.D. reported consultant, Cook Medical; and honoraria, Edwards Lifesciences and Medtronic.M.A.M. reported consultant, honoraria, and research with Medtronic, Edwards Lifesciences, ZMedica, AtriCure, JOMDD, and Abbott Laboratories.P.P. reported funding from Edwards Lifesciences, Medtronic, Pi-Cardia, and Cardiac Success for echocardiography core laboratory analyses and research studies in the field of transcatheter valve therapies, for which he received no personal compensation; and lecture fees from Edwards Lifesciences and Medtronic.All other authors 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.25.Malvindi PG, Mastro F, Kowalewski M, Ringold M, Margari V, Suwalski P, et al.Durability of mitral valve bioprostheses: a meta-analysis of long-term follow-up studies.Ann Thorac Surg.2020;109:603-11.
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TABLE E1 .
Institutional review board approvalsIRB/EC, Institutional review board/ethics committee.