Percutaneous MitraClip Device or Surgical Mitral Valve Repair in Patients With Primary Mitral Regurgitation Who Are Candidates for Surgery: Design and Rationale of the REPAIR MR Trial

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: MitraClip; REPAIR MR; cardiovascular diseases; heart valve diseases; mitral regurgitation; mitral valve insufficiency; mitral valve repair.

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.

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).

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.

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.

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.

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.