The North American EVEREST (Endovascular Valve Edge-to-Edge Repair Study) trials represent the safety and feasibility (EVEREST I) and pivotal (EVEREST II) MitraClip trials, which established the initial algorithms for clinical and echocardiographic patient selection and the procedural protocols and utilized echocardiographic core-lab follow-up.

The EVEREST I safety and feasibility trial enrolled 55 subjects and was reported with an additional 52 patients treated in the pre-randomization start-up (roll-in) phase of the EVEREST II pivotal trial [26]. Patients were selected if they were candidates for MV surgery, met major ACC/AHA indications for MV surgery, and had very specific echocardiographic criteria including a primary central regurgitant jet associated with the A2/P2 segments, a leaflet coaptation length ≥2 mm, a coaptation depth ≤11 mm, a flail gap <10 mm, and a flail width <15 mm. Key exclusion criteria included LVEF ≤25 %, LV end-systolic dimension >55 mm, mitral valve orifice area <4 cm², or recent myocardial infarction. Of the 107 patients who underwent the MitraClip procedure in this early clinical experience, 70 (74 %) achieved acute procedural success (APS), defined as a post-procedure reduction of MR to ≤2+. Of subjects who did not achieve APS, 17 (16 %) had MitraClip implantation with acute MR grade >2+, and 11 (10 %) had no MitraClip implanted with post-procedure MR > 2+. At 12 months, not including crossover to surgery, 50 of 76 APS patients (66 %) had echocardiographic follow-up and continued with MR ≤ 2+. A total of 32 patients underwent MV surgery after a clip procedure, and when repair was planned, 84 % were successfully repaired. Freedom from death at up to 3 years follow-up was 90.1 %, and freedom from surgery was 76.3 %. The majority of patients included had degenerative MR (79 %), but patients with functional MR (21 %) had similar acute results and durability.

The landmark EVEREST II trial was the first randomized trial of a percutaneous mitral repair device measured against conventional surgical therapy and also represents the first echocardiographic core-lab adjudicated follow-up after surgical mitral valve repair [27]. This trial randomized 279 patients with 3–4+ MR amenable to surgical repair prospectively to receive either MitraClip therapy (n = 184) or conventional surgical repair or replacement (n = 95) in a 2:1 ratio. The primary safety endpoint was any major adverse event (MAE) at 30 days. Prespecified MAEs were death, major stroke, reoperation of mitral valve, urgent/emergent CV surgery, myocardial infarction, renal failure, deep wound infection, ventilation >48 h, new onset permanent atrial fibrillation, septicemia, GI complication requiring surgery, or transfusion ≥2 units. The composite primary efficacy endpoint was defined as 12-month-freedom death, new surgery for mitral valve dysfunction, or MR > 2+. The intention-to-treat 30-day MAE rate was lower in the MitraClip group when compared to the surgery group (15 % vs. 48 %, superiority P < 0.001). The MAE difference was driven largely by transfusion requirements in the surgical arm; however, in response to this criticism, a modified MAE analysis which defined major bleeding as transfusion ≥4 units or requiring surgical intervention still demonstrated a lower MAE rate in the MitraClip group (5.0 % vs. 30.9 %, P < 0.0001) [28]. Primary clinical efficacy at 12 months by intention to treat was achieved in 55 % of the MitraClip device patients and 73 % of the surgery group (non-inferiority P = 0.007). After 2-year follow-up, primary clinical efficacy was preserved in 52 % of the percutaneous-repair group and 66 % in the surgery group (P = 0.04, non-inferiority). There was no need for emergency surgery in any patient treated with MitraClip therapy. It is important to emphasize that the EVEREST II trial examined the safety and efficacy of MitraClip therapy as an initial strategy in the treatment of patients with MR. Not every MitraClip procedure was successful in reducing MR, but of these failures in reaching acute procedural success, the majority went on to have successful subsequent mitral valve surgery. Both the MitraClip and surgically treated subjects had favorable LV remodeling and improvements in quality of life at 12 months. A non-prespecified subgroup analysis showed that for subjects with age ≥70 years, functional MR, and LVEF <60 %, surgery was not superior to percutaneous treatment with regard to efficacy. Concomitant with the EVEREST II trial, a single-arm “high risk registry” (HRR) enrolled 78 patients with primarily FMR and an STS or surgeon-estimated surgical procedural mortality risk of ≥12 %. The HRR demonstrated superior safety compared to the estimated surgical risk, as well as favorable LV remodeling and improved symptoms in most patients.

It is desirable that subsequent surgical options for MV repair are preserved after MitraClip implantation. This is most important in low surgical risk patients with degenerative MR. However, it is debatable whether mitral valve repair after a failed MitraClip procedure in functional mitral regurgitation should even be attempted, as a mortality difference has not been shown between repair and replacement in patients with ischemic MR up to 6 years after surgery [29]. Nonetheless, it has been shown that surgical repair can be performed in many subjects successfully after MitraClip therapy, with successful repair having been reported up to 5 years after implantation [30, 31]. It is clear that not every patient will be able to have successful surgical repair after MitraClip therapy, and it is very likely that fibrosis over time will hinder successful clip removal without injuring the leaflets. The degree to which this limitation will be clinically significant requires further study. The presence of anterior/bileaflet flail or prolapse has been shown to be a significant predictor of the need for MV replacement. However, surgeon experience (defined as the number of surgeries performed annually), duration of implant, or an operative note of valve injury or difficulty removing the device did not have an impact on whether a repair or replacement was performed [32].

In March 2008, the MitraClip received CE-mark approval. Since then, the majority of MitraClip implants have been performed in Europe. In addition, the clinical characteristics of European patients are different from those enrolled in the EVEREST trials, as the relatively limiting mitral leaflet anatomic criteria were not consistently observed. The two largest reports to date on the European MitraClip experience emanate from a single center in Germany [33] and two centers in Italy [34], for a total of 82 patients. Both centers reported favorable acute and short-term outcomes in patients at high risk for surgery with primarily FMR and low ejection fractions. Data from the EVEREST trials and European registries are summarized in Table 28.2.

In the German experience, MitraClip therapy was used in 51 patients with ≥3 + MR who were at high risk for mitral valve surgery based on a logistic EuroSCORE >20, an STS score >12, or by other clinical factors which the team felt conferred a high surgical risk. Patients in this series had worse LV function and more adverse valve morphology than those enrolled in the EVEREST trials. Specifically, 35 patients (69 %) had LV or leaflet characteristics that would have excluded them from enrollment in the EVEREST trials. Despite these adverse characteristics, acute outcomes were favorable, with reduction in MR severity two or more grades in 65 % of subjects and no clinically significant mitral stenosis, procedure-related major adverse events, or inhospital mortality. Longer-term outcomes from this cohort have not been reported, and therefore effects on prognosis and durability of left ventricular remodeling and MR reduction remain unanswered.

In two Italian centers, 31 subjects who were high risk for surgery underwent MitraClip therapy. Although clinical and anatomic leaflet criteria were similar to the EVEREST trials, there was no exclusion for very low LV ejection fraction or severe LV enlargement. Acute device success was observed in 97 % of patients, with sustained MR reduction and favorable LV remodeling seen at 30 days. The higher acute success rates in this series as compared to the EVEREST trials may reflect the lack of a blinded core lab, a different patient population, more liberal use of two clips, and an accelerated procedural learning curve as a result of prior experience in North America. Longer-term efficacy and durability in this initial cohort has not yet been reported. Hopefully the ongoing North American REALISM registry will validate these outcomes.

The MitraClip has emerged as an important therapeutic option for patients with mitral regurgitation. The device has excellent safety; acute outcomes are favorable, and for those patients with acute procedural success, midterm durability (up to 2 years) is reasonable. For patients at low surgical risk with degenerative MR, surgical mitral valve repair has set a high standard, with a 10-year freedom from reoperation of up to 97 % [35]. Based on adoption patterns in Europe, recent utilization trends in North America, and subgroup analyses from the EVEREST II trial, it would appear that patients who are older, at higher risk for surgical therapy, or with functional MR and depressed ejection fractions will constitute the initial target population for MitraClip therapy. Since functional MR is primarily a ventricular problem, it remains to be seen whether a pure leaflet intervention will have durable efficacy or will be superior to best medical therapy with cardiac resynchronization therapy. If so, a very large population of patients could benefit. The potential importance of concomitant annuloplasty as an adjunct to MitraClip remains unanswered. Failure to perform annuloplasty at the time of surgical degenerative leaflet repair has been shown to adversely affect repair durability [36–38]. Future iterations of the MitraClip may simplify leaflet insertion and grasping. 3-D transesophageal echocardiography (TEE), which was not widely available at the outset of the MitraClip experience, has been shown to lessen procedure times and improve visualization [39].