Abstract
Background
The current standard of care for the treatment of patients with primary mitral regurgitation (MR) is surgical mitral valve repair. Transcatheter edge‐to‐edge repair with the MitraClip device provides a less invasive treatment option for patients with both primary and secondary MR. Worldwide, >150 000 patients have been treated with the MitraClip device. However, in the United States, MitraClip is approved for use only in primary patients with MR who are at high or prohibitive risk for mitral valve surgery. The REPAIR MR (Percutaneous MitraClip Device or Surgical Mitral Valve Repair in Patients With Primary Mitral Regurgitation Who Are Candidates for Surgery) trial is designed to compare early and late outcomes associated with transcatheter edge‐to‐edge repair with the MitraClip and surgical repair of primary MR in older or moderate surgical risk patients.
Methods and Results
The REPAIR MR trial is a prospective, randomized, parallel‐controlled, open‐label multicenter, noninferiority trial for the treatment of severe primary MR (verified by an independent echocardiographic core laboratory). Patients with severe MR and indications for surgery because of symptoms (New York Heart Association class II–IV), or without symptoms with left ventricular ejection fraction ≤60%, pulmonary artery systolic pressure >50 mm Hg, or left ventricular end‐systolic diameter ≥40 mm are eligible for the trial provided they meet the moderate surgical risk criteria as follows: (1) ≥75 years of age, or (2) if <75 years of age, then the subject has a Society of Thoracic Surgeons Predicted Risk Of Mortality score of ≥2% for mitral repair (or Society of Thoracic Surgeons replacement score of ≥4%), or the presence of a comorbidity that may introduce a surgery‐specific risk. The local surgeon must determine that the mitral valve can be surgically repaired. Additionally, an independent eligibility committee will confirm that the MR can be reduced to mild or less with both the MitraClip and surgical mitral valve repair with a high degree of certainty. A total of 500 eligible subjects will be randomized in a 1:1 ratio to receive the MitraClip device or to undergo surgical mitral valve repair (control group). There are 2 co–primary end points for the trial, both of which will be evaluated at 2 years. Each subject will be followed for 10 years after enrollment. The study has received approval from both the Food and Drug Administration and the Centers for Medicare and Medicaid Services, and enrolled its first subject in July 2020.
Conclusions
The REPAIR MR trial will determine the safety and effectiveness of transcatheter edge‐to‐edge repair with the MitraClip in patients with primary MR who are at moderate surgical risk and are candidates for surgical MV repair. The trial will generate contemporary comparative clinical evidence for the MitraClip device and surgical MV repair.
Registration
https://clinicaltrials.gov/ct2/show/NCT04198870; NCT04198870.
Keywords: cardiovascular diseases, heart valve diseases, MitraClip, mitral regurgitation, mitral valve insufficiency, mitral valve repair, REPAIR MR
Subject Categories: Clinical Studies, Valvular Heart Disease
Clinical Perspective.
What Is New?
This prospective, multicenter, randomized controlled trial compares clinical outcomes of traditional surgery to transcatheter edge‐to‐edge repair with the MitraClip in moderate‐risk and elderly (≥75 years of age) patients with severe primary mitral regurgitation.
The study will report a 10‐year follow‐up on outcomes and is designed to demonstrate noninferiority of the MitraClip to surgery (the current gold standard treatment of primary MR).
What Are the Clinical Implications?
A randomized clinical trial will add new knowledge on safety and efficacy of transcatheter treatment of severe primary mitral regurgitation in a Medicare population.
Nonstandard Abbreviations and Acronyms
- MR
mitral regurgitation
- MV
mitral valve
- REPAIR MR
Percutaneous MitraClip Device or Surgical Mitral Valve Repair in Patients With Primary Mitral Regurgitation Who Are Candidates for Surgery
- STS
Society of Thoracic Surgeons
- TEER
transcatheter edge‐to‐edge repair
- TR
tricuspid regurgitation
- TVT
Transcatheter Valve Therapy
Primary (or degenerative) mitral regurgitation (MR) occurs because of primary abnormality of the mitral valve (MV) leaflets or chordae tendineae. Although rheumatic heart disease and other inflammatory conditions may cause primary MR, its most common underlying cause in developed countries is mitral valve prolapse or flail leaflet caused by chordal rupture resulting in type II leaflet motion per Carpentier's classification (Figure 1). Mitral valve prolapse is the most common organic MV pathology and is found in approximately 2.5% of adults in the United States. 1 Although this pathology does not progress to clinically significant MR in most patients, those who develop symptoms attributable to MR have a worse prognosis, with progressive left ventricle dysfunction and congestive heart failure, 2 and advanced cases have mortality rates of up to 34% annually.
Figure 1. Primary mitral regurgitation.
Primary (or degenerative) mitral regurgitation occurs because of a primary abnormality of the mitral valve (MV) apparatus, where one or both leaflets of the MV are impaired such as leaflet prolapse (left) or flail leaflet caused by chordal rupture (right), and is also referred to as type II in Carpentier classification.
Undertreatment of MR
Approximately half of all patients with symptomatic severe MR do not receive surgery because of perceived elevated operative risk, which may be from advanced age, comorbidities, or impaired left ventricle function. 3 , 4 A community cohort study from the Mayo Clinic showed a high prevalence of untreated primary MR, and only 29% of patients underwent MV surgery. 5 Mortality and heart failure were elevated in untreated patients. Just as transcatheter aortic valve replacement addressed the undertreatment of many patients with aortic stenosis, the REPAIR‐MR (Percutaneous MitraClip Device or Surgical Mitral Valve Repair in Patients With Primary Mitral Regurgitation Who Are Candidates for Surgery) trial will investigate if a less invasive procedure, transcatheter edge‐to edge repair (TEER), may alleviate the treatment gap for older and moderate‐risk primary patients with MR.
Current Treatment Options: Surgery
The American Heart Association/American College of Cardiology guidelines and the European Society of Cardiology guidelines 6 , 7 note that MV repair is preferred over replacement for patients with primary MR (not including rheumatic or inflammatory diseases) when a durable repair is expected (class I, level of evidence B). The clinical and survival benefits of MV repair over replacement have been documented for years. 8 Hendrix et al and Vassileva et al compared 30‐day outcomes between patients receiving MV repair versus MV replacement for primary MR in elderly populations. 9 , 10 Hendrix et al showed that in patients >70 years of age, repair was associated with lower operative mortality compared with MV replacement (2.2% versus 4.8%). Vassileva et al reported 3.9% (MV repair) versus 8.9% (MV replacement) 30‐day mortality, with sustained survival differences through 10 years. 9 Approximately 83% of patients with primary MR of all ages in the Society of Thoracic Surgeons (STS) database undergoing MV surgery for primary MR have their valves repaired. 11
Surgical repair has historically been performed by leaflet resection or neochord implantation, in conjunction with insertion of an annuloplasty ring (Figure 2), to facilitate leaflet coaptation and reestablish MV competence. 12 However, there has been continuous evolution in surgical techniques over the years as more is discovered about the MV's dynamic structure and function. 13 , 14 A successful surgical repair is expected in the surgical arm of REPAIR MR and consists of: (1) restoration of adequate coaptation surface of the leaflets, (2) maintenance of full leaflet motion, and (3) stabilization of the annulus (annuloplasty) to ensure at most only trace‐to‐mild MR is present at the completion of surgery, as documented by intraoperative transesophageal echocardiogram. 14
Figure 2. Mitral valve repair to restore leaflet coaptation.
Mitral valve repair is typically performed by resection of the posterior leaflet (left) with reconstruction or artificial chordae to the anterior leaflet (center). An annuloplasty ring is an important addition to create the right amount of leaflet coaptation (right).
Early mitral repair for asymptomatic patients constitutes only 6.5% of all mitral repairs in the United States but can be much higher in centers of excellence. 11 , 15 Also, advanced patient age and comorbidities impact referral to surgery, as well as symptoms. 16 In real‐world surgical practice, late patient referral until left ventricle function has deteriorated, resulting in impaired postsurgical survival, is not uncommon. 17 Other preoperative factors associated with late presentation of primary MR (ie, low left ventricular ejection fraction, advanced New York Heart Association class, atrial fibrillation, and tricuspid regurgitation [TR] predict 30‐day and late mortality in the elderly). 18
Current Treatment Options: TEER With the MitraClip System
TEER with the MitraClip device is a less invasive treatment option for patients with MR. The most recent American Heart Association/American College of Cardiology guidelines provide a class IIa recommendation for percutaneous MV repair in patients with degenerative MR, stating it may be considered for “severely symptomatic patients (New York Heart Association class III or IV) with primary severe MR and high or prohibitive surgical risk, TEER is reasonable if MV anatomy is favorable for the repair procedure, and patient life expectancy is at least 1 year.” 7 These guidelines are consistent with the current US Food and Drug Administration indication for MitraClip device use in patients with primary MR. Based on the evidence from the TVT (transcatheter valve therapy) registry contemporary publications, 19 , 20 , 21 , 22 MitraClip has been used predominantly for the treatment of patients with primary MR with high/prohibitive surgical risk, per the approved Food and Drug Administration indication.
TEER with the MitraClip is achieved by deploying a clip that grasps and coapts the anterior and posterior MV leaflets, thereby reducing or eliminating MR at the location of the prolapse or flail leaflets. The MitraClip G4 system, the current generation system in the REPAIR MR trial, is shown as part of Figure 3. The MitraClip is aligned with the arms perpendicular to the line of coaptation. The mitral leaflets are grasped and the device is closed, resulting in fixed approximation of the mitral leaflets. Before MitraClip deployment, the leaflet insertion, the degree of MR reduction, and pressure gradients are assessed by transesophageal echo and hemodynamic measures to ensure acceptable MR reduction without valvular stenosis.
Figure 3. The MitraClip G4 delivery system and the associated 4 clip sizes.
The current MitraClip G4, shown in the upper panel, is a fourth‐generation clip delivery system. In the lower panel, the 4 available clip sizes are shown: NT (same length and width as the initial and prior generation systems), NTW (same length, wide arm), XT (long length and standard width), and XTW (long length and wide arm). The size range allows physicians to tailor therapy to individual patient anatomy.
Clinical Outcomes With the MitraClip System
Outcomes with the MitraClip have been described in studies starting with the EVEREST (A Study of the Evalve Cardiovascular Valve Repair System Endovascular Valve Edge‐to‐Edge REpair Study) 23 series of trials and most recently from the multicenter Global EXPAND (A Contemporary, Prospective Study Evaluating Real‐world Experience of Performance and Safety for the Next Generation of MitraClip® Devices) 22 and COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) studies. 24 Since the EVEREST II Randomized Clinical Trial, outcomes have steadily improved with the MitraClip system as reported on the EVEREST II REALISM (A Continued Access Registry of the Evalve MitraClip System: EVEREST II Real World Expanded Multicenter Study of the MitraClip System) registries, as well as other postmarket studies. Device implant rates are now approaching 100%. 25 Most importantly, with the introduction of the next generation MitraClip NTR and XTR systems, approximately 87% of the patients have mild (1+) or less MR, 26 compared with only 43% observed during the EVEREST II trials. In patients who do not have complex lesions in the EXPAND study, MR was reduced to ≤1+ in 88.8%. The current MitraClip G4 system provides expanded abilities for the operator to repair the valve with 2 additional clip sizes (4 total), the ability to independently grasp each leaflet, and left atrial pressure monitoring during the procedure (Figure 3). Outcomes with the MitraClip system have been recently reported in both single‐center 27 and multicenter studies, 28 with >90% experiencing an MR reduction to mild or less (1+). Such improvement in outcomes over time can be attributed to greater clinical experience with the system, improvements in 3‐dimensional intraprocedural echocardiographic imaging, and improvements with the MitraClip system itself.
Clinical Evidence Gaps in the Treatment of Primary MR
Although there is extensive worldwide clinical experience with both surgery and MitraClip for primary MR, the literature primarily consists of nonrandomized, single‐center, or registry reports, many with limited follow‐up. Publication bias is likely and outcomes assessed by echocardiography core labs are rare. Early recovery of patients with less invasive surgery should be explored and compared with the MitraClip, and the late outcomes of concomitant surgery for atrial fibrillation, left atrial appendage closure, and moderate tricuspid regurgitation should be investigated. Finally, the clinical impact of residual or recurrent moderate MR in both groups needs to be clarified and compared because it is an area of vigorous debate with little evidence. The REPAIR MR trial will address this evidence gap to understand the best therapy for older and moderate risk patients.
Rationale for the REPAIR MR Trial
Although years ago, the early MitraClip device was not found to be as effective as MV surgery for treating primary MR in the EVEREST II Randomized Clinical Trial, the rationale for conducting REPAIR MR in this better‐defined older or moderate risk patient population is as follows:
Current clinical practice and outcomes with the MitraClip device, in terms of patient selection, MR reduction, and procedural success, are likely reducing the gap in effectiveness compared with MV repair surgery. Current generation MitraClip systems (eg, Mitra Clip G4) may further improve the ease of use and achieve MR reduction outcomes that are closer to surgery in selected patients.
The quality of intraprocedural imaging has significantly improved, which allows operators better visibility for optimum grasping of MV leaflets.
The percutaneous MitraClip procedure is likely associated with fewer procedural complications, faster recovery, and a lower risk of cardiovascular hospitalizations compared with surgery.
The minimally invasive MitraClip device may be an important alternative to MV surgery in this patient population and may address the undertreatment of older patients.
Finally, the clinical experience of MitraClip operators is much greater today than when the EVEREST II Randomized Controlled Trial was initiated. At experienced MitraClip sites today, surgery‐like outcomes are already being achieved with the MitraClip device as seen in the EXPAND registry.
Methods
Study Design and Objectives
REPAIR MR (registered at ClinicalTrials.gov, identifier NCT04198870; Data S1) is a prospective, multicenter, randomized controlled clinical trial, where the primary objective is to compare the clinical outcomes of the MitraClip device to surgical MV repair in subjects with severe primary MR (grade III or greater per the American Society of Echocardiography criteria as assessed by an echocardiographic core laboratory) who are at moderate surgical risk and whose MV has been determined to be suitable for correction by MV repair surgery by the cardiac surgeon on the local site heart team (Figure 4). The study is designed to demonstrate noninferiority of the MitraClip to MV repair surgery, which is currently the gold standard for the treatment of primary MR. All supporting data are available within this article and its Supplemental Material.
Figure 4. REPAIR MR enrollment schema.
The enrollment process for REPAIR MR begins with identification of a symptomatic patient ≥75 years of age with severe primary MR per ASE criteria. The inclusion and exclusion criteria are applied, and the patient is further reviewed by the site heart team (for determination of high degree of surgical success) and the eligibility committee (to confirm MR can be reduced to mild or less with the MitraClip or surgery). Subjects are then randomized 1:1 to either the MitraClip or surgical mitral valve repair (control group). ASE indicates American Society of Echocardiography; LVEF, left ventricular ejection fraction; LVESD, left ventricular end‐systolic diameter; MR, mitral regurgitation; PA, pulmonary artery; REPAIR MR, Percutaneous MitraClip Device or Surgical Mitral Valve Repair in Patients With Primary Mitral Regurgitation Who Are Candidates for Surgery; and STS PROM, Society of Thoracic Surgeons Predicted Risk of Mortality.
The REPAIR MR trial design and end points were developed by the study principal investigators, steering committee, and sponsor (Abbott, Santa Clara, CA) in accordance with the definitions outlined by the Mitral Valve Academic Research Consortium. This investigational device exemption trial is approved by the Food and Drug Administration. The trial organization, leadership, committees, and core laboratories are listed in the Data S1. The REPAIR MR trial is funded by Abbott. Participating centers obtained approval by an institutional review committee, and subjects in the trial provide informed consent to participate.
Primary and Secondary End Points
The coprimary end points for the trial are (1) all‐cause mortality, stroke, cardiac hospitalization, or acute kidney injury requiring renal replacement therapy at 2 years (any cardiac hospitalizations in the first 30 days after treatment will be excluded), and (2) proportion of subjects with moderate or less MR (≤2+), without MV replacement, and without recurrent MV intervention (surgical or percutaneous) from the time of index procedure through 2 years (Table 1). The 2 coprimary end points were designed to investigate:
The clinical risk of each procedure
The effectiveness of each treatment in reducing MR
The impact of residual or recurrent MR on cardiac hospitalization and mortality
Table 1.
Primary and Secondary End Points for the Trial
Coprimary end point 1: All‐cause mortality, stroke, cardiac hospitalization, or acute kidney injury requiring renal replacement therapy at 2 years (any cardiac hospitalizations in the first 30 days after treatment will be excluded) |
Coprimary end point 2: Proportion of subjects with moderate or less MR (≤2+), without MV replacement, and without recurrent MV intervention (surgical or percutaneous) from the time of index procedure through 2 years |
Secondary end points:
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MR indicates mitral regurgitation; and MV, mitral valve.
Both coprimary end point 1 and coprimary end point 2 will be evaluated at 2 years of follow‐up and are designed to demonstrate noninferiority of the MitraClip to MV repair surgery. Both end points must be met to declare the trial to be successful.
There are 5 secondary end points in this study, aimed at demonstrating the benefit–risk of MitraClip versus MV repair surgery (Table 1). The primary procedural expectation for investigators in REPAIR MR is to reduce MR to mild or less with surgical repair or with the MitraClip. Hence, the first secondary end point compares MR reduction outcomes with the MitraClip with surgical repair (control group, which is also the gold standard). This end point will evaluate the noninferiority of MitraClip to surgical repair in the short term (30 days). The next 2 end points (length of hospital stay and proportion of subjects discharged home) evaluate the potential clinical benefit of treating patients with the less invasive MitraClip treatment. Both of these end points are important considerations for an elderly patient population, and hence MitraClip will be tested for superiority for these 2 end points. The fourth secondary end point is an assessment of quality of life improvement. Both MitraClip and surgical repair are expected to significantly improve quality of life in symptomatic patients; however, it is not known if the extent of quality of life improvement is the same between the 2 groups. This end point will be tested for noninferiority of MitraClip to surgical repair.
Finally, MV stenosis is a potential complication associated with both MitraClip and surgical repair. However, there may be a higher concern for severe symptomatic mitral stenosis in the MitraClip patients, especially if multiple clips are used. Hence, the fifth end point will evaluate the noninferiority of MitraClip to surgical repair. The secondary end points will be analyzed when all randomized subjects complete 2 years of follow‐up, similar to the coprimary end points.
Patient Population
The REPAIR MR trial will recruit male and female subjects who meet all of the inclusion criteria and none of the exclusion criteria for the trial in the United States, Europe, and Canada. At least 50% of the subjects will be enrolled in the United States. Patients with severe MR who are symptomatic (ie, New York Heart Association class II/III/IV), or asymptomatic with left ventricular ejection fraction ≤60%, pulmonary artery systolic pressure >50 mm Hg, or left ventricular end‐systolic diameter >40 mm, whose MV has been determined to be suitable for MV repair by the cardiac surgeon on the local site heart team, and in whom MR can be reduced to mild with a high degree of certainty with either the MitraClip device or MV repair surgery will be eligible for the trial.
Moderate surgical risk is defined as:
Patient is ≥75 years of age, regardless of STS Predicted Risk of Mortality
If patient is <75 years of age, the STS Predicted Risk of Mortality repair score has to be ≥2%, or if the STS score is <2%, the patient must have other comorbidities that may introduce a surgery‐specific risk.
Patient's general medical eligibility must be assessed by the site through interviews, medical record review, and any tests that are standard of care. Once the patient is determined to meet general eligibility criteria, they will be fully informed about the clinical investigation, and will be asked to sign an informed consent form if they wish to participate in the clinical investigation, followed by additional screening tests for confirmation of their eligibility for the trial.
Subject Screening, Enrollment, Randomization, and Follow‐Up
The overall trial design and flow are described as part of subject screening (Figure 5) and described in more detail in Data S2. The inclusion and exclusion criteria are outlined as part of Table 2. Subjects must meet all inclusion criteria and none of the exclusion criteria for consideration into the trial. In case the subject does not meet all inclusion criteria, or meets any of the exclusion criteria, the subject is considered a screening failure, and will not be able to participate in the clinical investigation.
Figure 5. REPAIR MR study flowchart.
Subject selection begins with approaching symptomatic patients with grade III or greater primary MR. Further inclusion and exclusion criteria screening (described in Figure 4) is performed, and the echo is reviewed by a core laboratory. Final review by the eligibility committee occurs before scheduling a baseline visit and randomizing the patient to the device group (MitraClip) or control group (mitral valve repair surgery). ASE indicates American Society of Echocardiography; MR, mitral regurgitation; MV, mitral valve; and REPAIR MR, Percutaneous MitraClip Device or Surgical Mitral Valve Repair in Patients With Primary Mitral Regurgitation Who Are Candidates for Surgery.
Table 2.
Inclusion and Exclusion Criteria
To be eligible for participating in the clinical investigation, subjects must meet all of the inclusion criteria and none of the exclusion criteria. |
Inclusion criteria |
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Exclusion criteria |
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ASE indicates American Society of Echocardiography; DVT, deep vein thrombosis; EC, eligibility committee; ECL, echocardiographic core laboratory; IABP, intra‐aortic balloon pump; IVC, inferior vena cava; LVEF, left ventricular ejection fraction; LVESD, left ventricular end‐systolic diameter; MR, mitral regurgitation; MV, mitral valve; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; and STS, Society of Thoracic Surgeons; and VAD, ventricular assist device.
Once the echocardiographic core laboratory has confirmed MR severity and the cause, an independent eligibility committee will evaluate if the MR can be reduced to mild or less with the MitraClip and MV repair surgery. If the eligibility committee determines that MR can be reduced to mild with the MitraClip, then the subject can be considered enrolled. Once approved, the subjects will be randomized in a 1:1 ratio to receive either the MitraClip device (device group) or undergo MV repair surgery (control group) according to a computer‐generated randomization scheme. Accordingly, subjects will have an equal chance of being assigned to the device group or the control group. The index MitraClip device procedure or MV repair surgery, per the subject randomization assignment, must be scheduled within 21 days after randomization. All subjects will be followed up for up to 10 years after the procedure.
Patients with mitral valve disease and coronary artery disease will also be included in the study, provided the coronary artery disease can be treated by bypass surgery or by percutaneous coronary intervention. If the patient is randomized to control, the patient will undergo coronary artery bypass surgery and mitral valve repair. On the other hand, if the patient is randomized to the device group, the patient will first undergo percutaneous coronary intervention, followed by transcatheter mitral valve repair a month later.
Statistical Analysis
Analysis Populations
Intention‐to‐Treat Population
The intention‐to‐treat population will consist of all subjects randomized in the cohort. All subjects will be analyzed in the group randomized regardless of the treatment received.
As‐Treated Population
The as‐treated population will consist of all subjects in the intention‐to‐treat population (device and control groups) with an attempted index procedure. Subjects will be analyzed in the group based on the index procedure attempted initially. Subjects who are randomized but did not have any procedure attempted will be excluded from the as‐treated population.
Primary End Points: Sample Size and Analysis Methodology
The trial is intended to demonstrate that TEER with the MitraClip device is noninferior to MV surgical repair for coprimary end point 1. The noninferiority margin is set at 10%. The expected event rate of this composite end point with surgical repair in this elderly patient population is approximately 25%. Assuming an attrition rate of 10% at 2 years follow‐up, a total sample size of 500 subjects with 1:1 randomization ratio (250 subjects in each group) will provide at least 80% power to test the coprimary end point 1, with a 1‐sided 5% significance level.
The trial is also intended to demonstrate that TEER with the MitraClip device is noninferior to MV surgical repair for coprimary end point 2. The noninferiority margin is set at 10%. Assuming the expected coprimary end point 2 success rate of 95% and an attrition rate of 10%, a sample size of 500 will provide at least 90% power to test the coprimary end point 2 using Farrington‐Manning score test with a 1‐sided 5% significance level. The analysis for both the coprimary end points will be performed on the ITT population, with the duration of follow‐up calculated from the date of randomization. The statistical analysis plan that further details the analysis methodology of this study is available from the corresponding author upon reasonable request.
Discussion
The REPAIR MR trial is the first randomized trial in patients with primary MR attributable to MVP comparing TEER using the MitraClip device with conventional surgical mitral valve repair who are ≥75 years of age or at moderate surgical risk. The trial is intended to evaluate whether the MitraClip device can be offered as a treatment option for these patients. Although intermediate surgical risk (or moderate risk) has been well defined for aortic stenosis, such a population is not well defined for mitral valve repair surgery, where operative mortality rates are much lower than those for surgical aortic valve replacement. 7 Consequently, the surgical risk stratification in the guidelines differ for surgical mitral valve repair and surgical aortic valve replacement. 7 The most recent guidelines define low surgical mitral repair risk as an STS repair score of <1% with no other comorbidities. The Food and Drug Administration approval for MitraClip is high surgical risk defined as an STS repair score of ≥6% or the presence of severe comorbidities that would present a surgery‐specific impediment. 7 Hence, the trial's steering committee concluded that the patient population should be defined as:
Any patient ≥75 years of age regardless of surgical risk
If a patient is <75 years of age, then the patient should have an STS repair score of 2% or the presence of other comorbidity that may introduce a procedure specific impediment.
It is important to note that REPAIR MR was not designed to enroll low‐risk patients, recently defined as <1% STS Predicted Risk of Mortality. Low‐risk patients with primary MR have a high repair rate (approaching 100%) in experienced centers, an exceptionally low 30‐day morbidity and mortality risk, excellent repair durability at 10 and 20 years in single‐center studies, 13 , 29 and late survival returned to that expected for a normal population. If such low‐risk patients who had been treated with TEER subsequently required an MV operation, they would most likely require replacement. 30
The rationale for the components of the end points are as follows:
Mortality: untreated primary MR is associated with increased risk of mortality. 5 , 9 Furthermore, MV repair surgery eliminates the increased risk of mortality and restores the natural life expectancy for the patient without MR. If the MitraClip eliminates MR or reduces MR to the same levels as surgery, then it should reduce the risk of mortality to the same levels as surgery.
Cardiac hospitalization: this component of the end point includes any cardiovascular hospitalization caused by heart failure, cardiac arrhythmias, pericardial/pleural effusion, and endocarditis. Importantly, any cardiac rehospitalization within the first 30 days after either procedure will be in a blanking period and not included in the primary end point analysis. Heart failure hospitalization is a potential consequence of untreated MR. If the MitraClip or surgery do not adequately treat the MR, there is a likelihood of increased heart failure hospitalizations.
Stroke: Stroke is a known major adverse event of cardiac surgery, with approximately 10% of elderly patients (≥75 years of age) experiencing a stroke over a 5‐year period after MV repair surgery. 18
Acute kidney injury: Similar to stroke, renal failure is a major adverse event, occurring in approximately 2% of the patients undergoing cardiac surgery, 61% of whom require dialysis. 9 The MitraClip is a less invasive treatment option that may reduce the risk of acute kidney injury.
The rationale for the components of coprimary end point 2 is shown below.
Moderate or Less MR (≤2+) at 2 Years
Both the MitraClip and surgical MV repair are expected to procedurally reduce MR to mild or less (≤1+) within the REPAIR MR trial based on patient and site selection. Recurrent, stable, moderate MR at 2 years is physiologically different than moderate MR left at the time of the procedure (surgery or MitraClip). Residual moderate MR determined by transesophageal echo during surgery is not an acceptable result and generally requires re‐repair until mild or less is achieved, or replacement if successful repair proves impossible. 31 , 32 For surgery, evidence is not clear on the impact of residual or recurrent 2+ MR on long‐term survival, cardiac hospitalizations, and new onset of atrial fibrillation, particularly for the older patients >75 years of age. In one such analysis, 2+ recurrent MR had no impact on 10‐year survival. 15 Data from the EVEREST II clinical trial show that although subjects with residual severe MR (3+/4+) after the procedure had worse prognosis compared with both mild and moderate MR, there was no difference in 5‐year mortality between mild and moderate MR landmarked at 1 year (Figure 6). Potential adverse clinical outcomes associated with residual or recurrent 2+ MR will still be accounted for in the primary end point (congestive heart failure, rehospitalization, progression requiring intervention with a MitraClip, surgery, transcatheter mitral valve replacement, or transcatheter mitral valve in ring). Secondary end points, such as quality of life, also may detect clinically significant differences. If the echo finding of moderate MR without clinical events was in the primary end point, then the echo finding would be at the same level as serious clinical events such as death and stroke. Ten‐year follow‐up data will adequately address the gap in our understanding of the clinical impact of residual/recurrent MR. The frequency of occurrence of moderate MR and its clinical associations will likely be a separate article at 2 years follow‐up, and again at 5 and 10 years, because this has been an area of interest with little core laboratory adjudicated data to guide us.
Figure 6. Totality of EVEREST II primary MR clinical experience (randomized clinical trial, high‐risk registry, and REALISM continued access study) stratified by MR severity landmarked at 1 year.
Data from the EVEREST II clinical trial (pooled from the randomized clinical trial, high‐risk registry, and continued access studies) demonstrated no difference in 5‐year mortality between subjects with residual severe MR compared with either mild or moderate MR. EVEREST indicates A Study of the Evalve Cardiovascular Valve Repair System Endovascular Valve Edge‐to‐Edge Repair Study; MR, mitral regurgitation; and REALISM, A Continued Access Registry of the Evalve MitraClip System: EVEREST II Real World Expanded Multicenter Study of the MitraClip System.
Without MV Replacement and Without Recurrent MV Intervention
Subjects enrolled in the study are expected to have MV anatomy that is suitable for MV repair (MitraClip or surgery) where there is a high probability (>95%) for the operator to achieve MR of 0 or 1+. As such, the need for MV replacement (at the time of the index surgical procedure) is expected to be low. It is understood that surgeons should replace the valve if they would otherwise have to leave residual moderate or more MR, whereas a MitraClip operator may occasionally leave the subject with residual MR of 2+. If such a subject does experience symptomatic severe MR and undergoes reintervention with an additional clip (a procedure that will likely be undertaken because of its underlying safety) or a surgical reintervention (also a likely option because the patient has not undergone surgery), then it will be counted as a failure of the end point. Hence, to appropriately balance the end point of MV replacement, MV reintervention (percutaneous or surgical) after the index procedure was also added.
In summary, a subject would be considered a success with respect to the primary end points if the subject is:
Alive, with no cardiac rehospitalizations, no stroke, and no acute kidney injury at 2 years
Has moderate or less MR and did not undergo any MV reintervention at 2 years
The trial will be considered a success only if both the coprimary end points are met.
The REPAIR MR trial will be dependent on whether the right sites have been selected for the trial. Studies have previously demonstrated an association between success and procedural volume for both procedures. 33 , 34 To drive equitable outcomes between mitral valve surgery and MitraClip, participating institutions must have surgeons who perform at least 25 mitral valve surgeries annually or TEER operators who perform at least 25 MitraClip procedures annually. Given the trial's objective to compare outcomes with the standard of care, the top 20 mitral valve centers by surgical volume were identified using the Medicare claims data and invited to the trial. Greater than 50% of the sites have accepted the invitation to participate in the trial. Priority has been given to selecting mitral valve centers of excellence to ensure that best in class outcomes are achieved with surgical mitral valve repair.
REPAIR MR will add new, contemporary, and important clinical information. Patients, clinicians, and payors will want data documenting the difference in recovery between groups on complications, length of stay, discharge to home, and quality of life. 15 , 32 , 35 Various surgical approaches will be used (eg, right thoracotomy, robotics, sternotomy) and recovery between these groups will be conducted. Repair rates are high in centers of excellence, 13 , 36 , 37 but the rate of surgical repair in a multicenter study in this population has not been reported, and residual/recurrent MR has not been systematically studied or assessed by a core laboratory over 10 years. In both groups, the late clinical impact of recurrent MR or mitral stenosis have not been studied prospectively in this population. Patients with primary MR frequently have associated atrial fibrillation and moderate TR (patients with severe TR are excluded from the study). In the surgical group, concomitant AF ablation, left atrial appendage occlusion, and treatment of concomitant less than severe TR may be performed, which may impact late outcomes such as stroke, re‐hospitalization, reintervention for TR, and possible survival. 38 Concomitant procedures will not be allowed in MitraClip‐treated patients, but transcatheter approaches may be performed at a later follow‐up as appropriate.
In conclusion, REPAIR MR is expected to be a landmark, guideline‐impacting, randomized controlled trial that will generate contemporary clinical evidence for TEER and surgical repair of primary MR in patients who are at moderate surgical risk or ≥75 years of age regardless of surgical risk score. A significant majority of patients enrolled in the trial are expected to be older, a population that is significantly undertreated. The trial, if successful, may provide a minimally invasive treatment option for an underserved patient population.
Sources of Funding
This work was supported by Abbott and designed collaboratively by the principal investigators for the REPAIR MR trial and Abbott.
Disclosures
P.M.M.: Abbott, co–principal investigator of REPAIR‐MR (unpaid); Abbott and egnite, advisory board; Edwards Lifesciences, royalties; Medtronic, Edwards Lifesciences, Atricure, speaker fees. B.W.: Abbott and Edwards Lifesciences, consulting fees. A.W.A.: Gore, Medtronic, Edwards Lifesciences, Abbott, consulting fees. J.H.: Abbott, consulting fees; Edwards, consulting fees, Medtronic, consulting fees. M.W.: Abbott, Medtronic, Boston Scientific, Edwards Lifesciences, research funding. A.M.: none. M.R.: Edwards, consultant, speaker, advisory board, proctor; Abbott: consultant, speaker, proctor; Boston Scientific, consultant, speaker, advisory board, research grant. P.G.: Abbott Vascular, Boston Scientific, Cardiovalve, Edwards Lifesciences, Medtronic, Neochord, W. L. Gore, 4C Medical, research grants; Abbott Vascular, Cardiovalve, Edwards Lifesciences, Medtronic, Neochord, W. L. Gore, 4C Medical, consultant/advisory boards. J.D.T.: Abbott, egnite, Caption Health, EchoIQ, consultant. R.M.: Abbott, advisory board; Edwards Lifesciences, speakers bureau; Medtronic, advisory board, speakers bureau; Caption Health, stockholder and officer. F.M.A.: none. His work as Director of an Academic Core laboratory is through institutional research grants (MedStar Health) with Abbott, Boston Scientific, Medtronic, Edwards Lifesciences, Neovasc, Ancora Heart, Livanova, MVRx, InnovHeart, Polares Medical, and Aria CV. Y.S.: Abbott, employment. K.S.: Abbott, employment. N.M.: Abbott, employment. S.K.: Abbott, grants and institutional research support; Boston Scientific, Edwards Lifesciences, Abbott, Boston Scientific, W.L. Gore; Medtronic, consulting fees/honoraria; Abbott, steering committee member of TRILUMINATE (Trial to Evaluate Treatment With Abbott Transcatheter Clip Repair System in Patients With Moderate or Greater Tricuspid Regurgitation); Abbott, co‐principal investigator EXPAND; Abbott, co‐principal investigator REPAIR MR.
Supporting information
Supporting information S1–S2
Acknowledgments
The authors thank J. Kruse for her assistance with the article and submission.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.122.027504
For Sources of Funding and Disclosures, see page 12.
Subject Terms: Clinical Studies; Valvular Heart Disease.
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Supplementary Materials
Supporting information S1–S2