Review Article
Percutaneous Mitral Heart Valve Repair—MitraClip Jay V. Doshi, MD,* Sahil Agrawal, MD,† Jalaj Garg, MD,† Rajiv Paudel, MD,† Chandrasekar Palaniswamy, MD,† Tina V. Doshi, DO,‡ William Gotsis, MD,† and William H. Frishman, MD†
Abstract: Mitral regurgitation (MR) is the most common cardiac valvular disease in the United States. Approximately 4 million people have severe MR and roughly 250,000 new diagnoses of MR are made each year. Mitral valve surgery is the only treatment that prevents progression of heart failure and provides sustained symptomatic relief. Mitral valve repair is preferred over replacement for the treatment of MR because of freedom from anticoagulation, reduced long-term morbidity, reduced perioperative mortality, improved survival, and better preservation of left ventricular function compared with valve replacement. A large proportion of patients in need of valve repair or replacement do not undergo such procedures because of a perceived unacceptable perioperative risk. Percutaneous catheter-based methods for valvular pathology that parallel surgical principles for valve repair have been developed over the last few years and have been proposed as an alternate measure in high-risk patients. The MitraClip (Abbott Labs) device is one such therapy and is the subject of this review. Key Words: percutaneous mitral valve repair, MitraClip, mitral regurgitation (Cardiology in Review 2014;22: 289–296)
M
itral regurgitation (MR) is the most common cardiac valvular disease in the United States. Approximately 4 million people have severe MR and roughly 250,000 new diagnoses of MR are made each year.1,2 MR results from impaired systolic coaptation of the leaflets. Ischemic and nonischemic diseases cause regurgitation via functional and/or organic mechanisms. The valvular apparatus is largely preserved in the former and regurgitation occurs via multiple mechanisms, including left ventricular (LV) dilation, impaired LV wall motion, and papillary muscle dysfunction. The natural progression of MR is characterized by an increase in the regurgitant volume by 5–7 mL/year manifested by a progressive increase in effective regurgitant orifice and annular dilation.3 Patients with mild to moderate MR may remain asymptomatic for many years; however, patients with severe symptomatic MR have a 5% annual mortality without valve surgery.4 Medical therapy is a temporizing measure and has not been shown to improve survival.5 Its use is limited to symptomatic control in heart failure. Mitral valve (MV) surgery is the only treatment that prevents progression of heart failure and provides sustained symptomatic relief.6 MV repair is preferred over replacement for the treatment of MR because of freedom from anticoagulation, reduced long-term morbidity, reduced perioperative mortality, improved survival, and better preservation of LV function compared with valve
From the *Department of Cardiology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY; †Department of Medicine, Division of Cardiology, New York Medical College, Westchester Medical Center, Valhalla, NY; and ‡Department of Family Medicine, Nassau University Medical Center, East Meadow, NY. Disclosure: The authors have no conflicts of interest to report. Correspondence: Jalaj Garg, MD, 100 Woods Road, PMB 495, Valhalla, NY 10595. E-mail: [email protected]. Copyright © 2014 Lippincott Williams & Wilkins ISSN: 1061-5377/14/2206-0289 DOI: 10.1097/CRD.0000000000000036
replacement.7–9 A large proportion of patients in need of valve repair or replacement do not undergo such procedures because of a perceived unacceptable perioperative risk.10,11 Percutaneous catheterbased methods for valvular pathology that parallel surgical principles for valve repair have been developed over the last few years and have been proposed as an alternate measure in high-risk patients.12,13 The MitraClip (Abbott Labs, Abbott Park, IL) device is one such therapy and is the subject of this review.
HISTORICAL BACKGROUND The techniques for MV repair first introduced by Carpentier14 in the 1970s have since provided durable results in MR of varied etiology. The technique primarily involved quadrangular leaflet resection for those with prolapse, transposition of normal chords to other areas of prolapsing leaflet tissue if needed, and a remodeling annuloplasty with complete ring prosthesis. The annuloplasty improves repair durability in degenerative MR15; and in functional MR the annuloplasty itself generally constitutes the whole repair procedure. The Alfieri stitch or the edge-to-edge technique was introduced in the 1990s as a simpler alternative to correct MR.16 Suture approximation of the leading edges of the leaflets at the site of regurgitation can reduce its severity without causing inflow obstruction. This can be supplemented with a prosthetic ring to stabilize the repair. The simplicity, easy-reproducibility, and effectiveness of this technique led to utilization of the edge-to-edge repair in MR patients of different etiologies. Appropriate patient selection achieved by a reliable preoperative anatomic and functional assessment on echocardiography is essential. As the MitraClip device is an application of this concept, it is important to review results of outcomes with its surgical predecessor. A long-term follow up of 133 patients with segmental anterior leaflet prolapse treated with the edge-to-edge repair was reported in 2006. Ten-year survivals, freedom from cardiac death and freedom from reoperation were very satisfactory with only a small minority of patients in New York Heart Association (NYHA) functional classes III or IV upon a long-term follow up. Mitral stenosis did not occur at surgery or on follow up. Edge-to-edge repair provided similar satisfactory clinical and echocardiographic results in 115 patients with commissural prolapse.17 A 1.7% incidence of reoperation, and a 4.7% incidence of moderate or more severe MR was demonstrated on a mean follw up of 2.3 ± 1.9 years. The use of the edge-to-edge technique was a significant determinant of repair durability in patients with functional MR, increasing the freedom from recurrence of MR from 77 ± 12.1% to 95 ± 3.4% when used concomitantly with an undersized annuloplasty ring.18 Absence of annuloplasty is likely to be associated with accelerated failure of the repair resulting from increased stresses on the suture and the valve structure.16 It remains to be seen if this will make a difference when using the MitraClip (which does not involve a concomitant annuloplasty). As a bail-out procedure in 53 patients, the Alfieri stitch documented excellent immediate and long-term results.19 Smaller MV areas postprocedure do not translate into functional mitral stenosis either at baseline or during exercise.20 Current indications for edge-to-edge repair include segmental anterior leaflet flail/prolapse, bileaflet prolapse (facing segments), commissural prolapse/flail, functional MR and miscellaneous (systolic anterior motion, hypertrophic cardiomyopathy,
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complex congenital atrioventricular valve incompetence), and special situations (rescue, poor exposure, beating heart mitral repair, severe LV dysfunction, concomitant multiple procedures, transaortic approach). Contraindications to edge-to-edge repair include no localized regurgitant jet, rheumatic MR, small MV area, and multiple mitral lesions involving nonfacing segments of the anterior and posterior leaflets. This technique has been subsequently used in over 1000 patients with MR of various etiologies, and has demonstrated durable clinical outcome.21 The MitraClip device is a percutaneous extension of the Alfieri technique and mimics the surgical technique of edge-toedge repair by utilizing a catheter-delivered clip rather than a suture to create the double orifice in an attempt to reduce the regurgitation jet.22 The success of the technique was first demonstrated in a porcine model.23 The first implantation in a human was performed in 2003.24 The device was Conformité Européenne marked in March 200825,26 and is currently investigational in the United States, and available only through the Real world ExpAnded MuLtIcenter Study of the MitraClip System (REALISM) continued-access registry. Almost 4500 patients have undergone the procedure across the United States and Europe.
EQUIPMENT AND PROCEDURAL TECHNIQUE The MitraClip device and the procedural technique have been previously described in detail27,28 (Fig. 1 and 2). The MitraClip uses a tri-axial system consisting of a MitraClip device (implant), a clip delivery system (CDS) and a 24-F steerable guide catheter (Fig. 3). The clip is attached to the tip of the disposable delivery catheter that passes coaxially through the guide. The clip is made of 2 polyester covered cobalt chromium arms that are roughly 8 mm long and 4 mm wide and have a span of approximately 2 cm when open. On the inner aspect of each arm are U-shaped “barbs” or “grippers” that
FIGURE 1. Double-orifice surgical MV repair with suture. Illustration depicts a double-orifice mitral valve (MV) surgical repair. The MV is viewed from the left atrial side. The middle scallops of the anterior and posterior leaflets have been sutured together, which creates a double orifice, edge-to-edge, or bow tie repair. (Reprinted with permission from Feldman et al28). 290 | www.cardiologyinreview.com
help stabilize the leaflets when each leaflet is secured between the closed arm and the corresponding gripper. The clip can be opened, closed, locked, and detached by a control mechanism on the delivery catheter handle. The procedure is performed in a cardiac catheterization laboratory with echocardiographic and fluoroscopic guidance. The patient is placed under general anesthesia and mechanically ventilated. Ussia et al29 and Teufel et al30 have recently reported the successful implantation of the clip device under conscious sedation and local anesthesia. The femoral vein is cannulated and a right heart catheterization is performed to document right heart pressures. A transseptal puncture is then performed using a Brockenbrough needle. Transseptal puncture using surgical diathermy has been recently described in a series of 66 patients.31 This is a critically important point in the procedure and transesophageal echocardiography (TEE) is crucial to establish an ideal site. This is supplemented by fluoroscopy and transthoracic echocardiography. Four key TEE views are used to provide basic guidance.32 The bicaval and short axis views are used in combination with the “four”-chamber view. This is essential to ensure adequate height above the valve plane, especially in degenerative disease where the line of coaptation is above the annular plane. The ideal site is posterosuperior in degenerative and anteroinferior in functional MR, with the trajectory directed posteriorly.26 The transseptal puncture is ideally performed 3.5–4.0 cm above the line of coaptation of valvular leaflets. Intravenous heparin is administered at this point to maintain an activated clotting time of around 250 seconds. A 0.035inch stiff guide wire is then passed into the left atrium through the transseptal catheter and exchanged for the steerable guide catheter. An echo-bright and radio-opaque ring identifies the tip of the floating catheter. The CDS is then advanced through the guide catheter into the left atrial chamber under TEE guidance and the clip is cautiously centered over the origin of the MR jet, carefully avoiding the aorta and the atrial wall. The clip is then rotated to achieve a position perpendicular to the line of leaflet coaptation at the origin of the MR. After ensuring satisfactory orientation, the clip is lowered into the LV. The CDS is then pulled back with the clip arms in the grasping position until the leaflets are captured. The grippers are dropped and the clip is partially closed to secure the leaflet. An assessment of the adequacy of leaflet insertion is warranted at this time before assessing for reduction in MR. After confirming an adequate grasp, the degree of MR is assessed before the clip is incrementally closed and the degree of residual MR is assessed. If the leaflet attachment or the degree of MR reduction is not satisfactory, the leaflets are released, the clip is withdrawn and repositioned before a second attempt. If satisfactory reduction of MR is achieved, the clip is deployed and released from the CDS and final TEE images are obtained. Right heart catheterization is performed to document hemodynamic parameters. If MR reduction is inadequate, the device allows for disengagement of the clip prior to complete deployment. The results of the valve repair can therefore be assessed in real time and multiple sites can be tested for an optimal result. The guide catheter and CDS are then removed when results are deemed satisfactory. Groin hemostasis is achieved by manual compression, closure devices or suturing after the activated clotting time has decreased appropriately. After the procedure, preloading is achieved with aspirin (325 mg in the United States) and clopidogrel (300 mg if there was no prior treatment, followed by aspirin 81 mg) for 6 months and clopidogrel (75 mg) for 1 month.33 If the patient is under chronic anticoagulation, no additional treatment is required (continue with a target internationalized normal ratio of 2–3). Currently, device therapy is not an independent indication for anticoagulation. Whether this will translate to a higher rate of paradoxical embolic events in the presence of lower rates of closure of iatrogenic atrial septal defects remains to be seen.34–36 It is unclear if prophylaxis for infective endocarditis is warranted; however, some authors recommend such a practice.26 © 2014 Lippincott Williams & Wilkins
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Percutaneous Mitral Valve Repair
FIGURE 2. The MitraClip device. The device is covered with polyester fabric to facilitate tissue in-growth. The distal gripping element helps with leaflet fixation. The clip delivery system exits through a guide catheter. (Reprinted with permission from Feldman et al28).
FIGURE 3. Patient selection criterion in EVEREST trial. The coaptation length must be at least 2 mm. Coaptation depth must be 25% and left ventricular systolic diameter ≤55 mm (3) Asymptomatic moderate-to-severe MR with LVEF 25–60% or left ventricular systolic diameter 40–50 mm or new onset atrial fibrillation (4) Pulmonary hypertension with pulmonary artery systolic pressure >50 mm at rest or >60 mm during exercise Exclusion criteria (1) Previous mediastinal surgeries (2) Mitral valve orifice area 48 hours, deep wound infection, septicemia, and new onset of atrial fibrillation (AF). Four-year follow up was complete in 161 patients (88%) in the device group and 73 patients (77%) in the surgical group. Sixty-eight patients (38.2%) received 2 devices during the index procedure. Nine patients were noted to have attachment of the device to a single leaflet during the first year with 1 additional incidence after 12 months. The rate of single leaflet attachment in practice is now closer to 1% compared with 5% in the trial. All these patients were treated with MV surgery (5 replacements and 5 repairs) with no device embolization. There was 1 postprocedural mitral stenosis at discharge (mean area, 1.5 cm and mean gradient, 14.5 mmHg). The patient eventually underwent MV replacement for recurrent MR 61 days after the original procedure. Five patients underwent an attempt to place a second MitraClip device through 12 months, with 4 of these being successful. Twenty-eight of 41 patients with initial unsuccessful percutaneous procedures and an additional 9 patients with an initially successful MitraClip but with late-onset device failure were referred to surgery. In the 12-month follow up, the outcomes of this subgroup were found to be similar to the original control group, thereby affirming that surgery is still viable and effective after a failed percutaneous procedure. The remaining patient underwent a successful implantation on an additional attempt between 12 months and © 2014 Lippincott Williams & Wilkins
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4 years of follow up. The primary safety end points at 12 months were observed in 9.6% and 57% in the device and control groups, respectively driven largely by a smaller need for blood transfusion which is expected with percutaneous therapy (8.8% vs 53.2% in the device and control groups, respectively, P < 0.0001). However, after adjusting for transfusion-related adverse events, the MitraClip still retained its superiority with regard to safety end points (0.7% vs 16.5%; P < 0.0001). An effective end point was reached in 39.8% in the percutaneous arm versus 53.4% in the surgical arm (P = 0.07). Similar rates of death (17.4% vs. 17.8%) and ≥3+ MR (21.7% vs. 24.7%) in the percutaneous repair and surgical groups were reported at 4 years of follow up. The rates of surgery for valvular dysfunction were 20.4% vs. 2.2% at 12 months and 24.8% vs. 5.5% over 4 years in the device versus surgical groups. However, the majority of surgical repairs after device therapy were encountered in the first year of follow up; and after the first year of follow up, there were similarly low rates of surgery required after either percutaneous or surgical treatment. This is in accordance with findings that the grade of MR generally remains stable beyond the first year of follow up. Surgical group patients experienced better MR reduction at discharge and at 4-year follow up than patients in the percutaneous repair group. Despite the more impressive improvements in MR grade with surgical repair, improvements in LV end-diastolic and end-systolic volumes of a similar magnitude were observed at 1 year and these were sustained at 4 years. Smaller LV end-diastolic diameters were noted in the surgical group at 4 years (4.84 ± 0.67 cm vs 5.25 ± 0.65 cm, P < 0.001). Similar improvements in NYHA functional class, as demonstrated by a decrease in the proportion of patients with class III or IV symptoms, were seen at 12 months and these improvements were persistent at 4 years. Functional MR is a greater operational challenge with surgical options that are more limited than for isolated leaflet pathology. Unlike degenerative MR, the relative benefit of surgery over medical therapy is less clear in MR of functional etiologies, and surgery is associated with more residual or recurrent MR.45 Sixty-six patients were found to have functional MR. Patients with functional MR experienced comparable effectiveness to surgery at 1 year and 4 years in exploratory analysis. Functional MR was more prevalent in the surgical arm in subjects with 3+ or 4+ MR at 4 years. In the EVEREST II trial, patients with MR of degenerative etiology derived greater benefit from surgery relative to percutaneous therapy compared with patients with functional MR. There is a trend for percutaneous therapy to be selected for patients with either functional MR outside of the US experience.46 The potential benefits of percutaneous MV replacement over surgical repair demonstrated in the study were (1) the reduction in MR was similar between the 2 interventions and (2) the reductions in MR grade and LV end-diastolic volume were significantly reduced with surgery compared to percutaneous MV replacement, but patients treated with percutaneous MV replacement demonstrated significantly reduced LV end-diastolic parameters with improvement in NYHA class and quality of life.44
Effects of Atrial Fibrillation in EVEREST II Trial MV surgery is a class IIa indication in patients with severe MR with new onset AF. AF which develops at a rate of approximately 5%1 in patients with MR portends a worse prognosis47,48 Varying rates of success have been noted in surgical series of patients with AF who undergo valve replacement or repair with similar49,50 or worse results51,52 demonstrated in different studies. Herrmann et al53 assessed the impact of AF on the outcomes of both the MitraClip procedure and surgical repair in a posthoc analysis of the EVEREST II trial. Of 264 patients, 72 had AF on the basis of their baseline © 2014 Lippincott Williams & Wilkins
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rhythm. Of these, 45 underwent percutaneous therapy with the MitraClip device. Patients with AF were older, had more medical comorbidities, a lower LVEF, and higher prevalence of NYHA classes III–IV symptoms. Functional MR (40% vs 19%) was more likely, however, MR grades were similar. Despite a seemingly more difficult procedure in the presence of an irregular rhythm, reduction of MR to ≤2+ was equally successful in patients with and without AF (83% vs 75%). Device attachment to a single leaflet occurred in 13% of AF patients versus 3% of non-AF patients. Freedom from death, MV surgery for valve dysfunction, and MR >2+, was similar for AF patients (64%), and non-AF patients (61%). A similar reduction in MR grade (to ≤2+) at discharge occurred in AF patients (97%) verus non-AF patients (85%). Freedom from all-cause mortality at 1 year did not differ by rhythm. Therefore, patients with MR and AF can expect similar benefits as their non-AF counterparts, and if found to meet clinical and echocardiography criteria, should be offered this therapy independent of the presenting rhythm. A greater difficulty in assessing leaflet insertion during echocardiography and additional caution to ensure leaflet insertion before clip release is, however, warranted.
EVEREST II High-Risk Registry All patients with elevated surgical risk secondary to comorbidities or previous cardiac surgeries were included in the EVEREST II high-risk analysis.54 The study population consisted of 78 high-risk patients with a predicted mortality of ≥12% [measured by the Society of Thoracic Surgery (STS) calculator]. All patients with LVEF ≤20%, unfavorable MV anatomy, LV end-systolic diameter >60 mm, and MVe area 4 cm2 and adequate leaflets tissue for mechanical coaptation. There are no clear indication criteria for the use of the MitraClip System (MCS), however, literature suggests (1) patients with symptomatic/ asymptomatic MR 3+ or 4+ with reduced LVEF, (2) multimorbidity, high-risk patient, contraindication for open MV surgery, log EuroSCORE >20% and/or STS score >12%, (3) AHA/ACC criteria for open MV valve surgery fulfilled, and (4) porcelain aorta or postradiation mediastinum.56–58 Possible indications for the use of MCS (1) symptomatic or asymptomatic MR 3+ or 4+ with normal LVEF and (2) younger patients (60 mm, transient ischemic attack or stroke within last 6 months, and myocardial infarction within last 3 months are ineligible for the procedure. If leaflet tethering is determined on echocardiogram, then coaptation depth >11 mm or vertical length 12% or patients deemed to be high risk for operation by surgeons by meeting ≥1 of prespecified criteria. Two major shortcomings were noted, however. Less than 62% patients were actually seen by surgeons before being included in the too high-risk group and 60% of the patients in these cohorts might not have been completely inoperable.61 Arguments were also made against pooling data from the 2 registries as they were conducted a year apart with subsequent differences in operator experience thereby possible.61 The 2 registries may have actually had patients with different risk categories given that major differences were noted between baseline characteristics (mean EF, MR etiology, and STS predicted risk). However, after entertaining these specific caveats, the panel agreed that this should not prevent premarket approval support for the intended population. A stricter criterion of MR ≤1+ at discharge as opposed to ≤2+ was suggested to be used for assessing effectiveness in EVEREST II by the FDA. A similar outcome was demonstrated when the pooled data from the high-risk registries were compared with data from the MCS-treated EVEREST II patients based on this new criterion. A deficiency of data on quality of life and use of heart failure medications remains and the limitation associated with interpreting the effectiveness in the absence of a suitable comparator must be acknowledged. A randomized-controlled trial similar to the Placement of Aortic Transcatheter Valves (PARTNER) trial would have been ideal to compare the merit of the device in this population that is too high risk for surgery.62 In summary, EVEREST II was unable to provide reasonable safety and effectiveness data in support of using the MCS in patients eligible for both therapies; and the ability of the single arm, high-risk registries to provide reliable and adequate data on too high-risk patients was found to be limited. The need for a palliative alternative for surgical high-risk patients was considered for the final risk/benefit vote. The MCS received FDA approval in October 2013 and is intended to treat patients with significant symptomatic degenerative MR with MR ≥3+ who have too high risk for surgery. 294 | www.cardiologyinreview.com
FUTURE DIRECTIONS While MV repair is an established treatment for degenerative MR, its role in the management of functional MR is unclear.63 The EVEREST trials investigated the new therapy in patients largely with degenerative MR. Surgical repair for functional MR currently has a IIb recommendation according to the AHA/ACC and European guidelines,64 Franzen et al65 demonstrated the feasibility of the MitraClip device in patients with severe LV dysfunction (EF ≤ 25%) and significant functional MR with a high logistic EuroSCORE. This was an important cohort of patients, as surgery has not been shown to have a survival benefit in this group with end stage heart failure.64 Their findings of a higher rate of MR reduction than the EVEREST cohort supports the hypothesis that percutaneous therapy might be more successful in treating functional MR. This finding is probably not surprising as functional MR patients usually have structurally normal thickness of their leaflets, etc., which probably makes it easier to grab the leaflets as compared to the degenerated leaflets of organic MR patients where it may be challenging. The acute reduction in MR severity was accompanied by sustained improvements in objective measures of symptom control and LV remodeling. Rates of 30-day mortality and 6-month survival similar to surgery and resynchronization therapy, respectively were also demonstrated. A European study expanded the use of the clip on an experimental basis to high surgical risk patients, 70% of whom would have been excluded in the original EVEREST trial either because of LV dysfunction or valve anatomy.66 The therapy was feasible in this cohort without major adverse events. As experience with the device increases, the possibilities of utilization of this percutaneous therapy continue to expand.67–70 Pleger et al71 successfully utilized device therapy as a tool for acute stabilization of high-risk patients who could subsequently be weaned off inotropic/ventilator therapy in the days following percutaneous valve repair. More recently, the MitraClip was successfully used as a less invasive option for prior failed annuloplasty instead of a higher risk reoperation for MR.72 The goal of surgery for MR is resolution of the regurgitation. The EVEREST trial did not aim for this and instead defined acute procedural success as reduction of MR to ≤2+. Paranskaya et al73 found that elimination rather than reduction of MR to ≤2+ resulted in better mortality outcomes. In addition to being safe and efficacious, a new percutaneous technique should not impede the safety or success of conventional surgery in the event of initial treatment failure. Argenziano et al74 reported that surgical options were largely preserved and successful repair was equally feasible as late as 18 months after clip implantation. Thirty-two patients enrolled in the EVEREST I and II trials underwent MV repair or replacement for various reasons after MitraClip therapy: 84% of planned repairs were successful; 11 patients had some degree of valve damage as a result of the procedure or clip removal. MV repair or replacement was performed as planned in all but 4 patients. Only 1 of these 4 patients had a replacement that was directly related to damage caused by the MitraClip procedure. These surgeries resulted in MR grade ≤2+ in all patients. Rogers et al75 reported successful surgical MV repair in a series of 4 patients up to 5 years after MitraClip implantation, therefore very late MV repair remains possible. It must be anticipated that an increasing number of percutaneous MV replacement procedures will be performed in the near future and more cases after failed intervention will occur. Therefore, surgical strategies may need to be adapted to this situation.
CONCLUSIONS Although limited clinical data have provided promising results for MitraClip implantation in the EVEREST trial irrespective of the etiology of MR, large randomized double-blind trials are needed to establish its clinical applicability. © 2014 Lippincott Williams & Wilkins
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24. Condado JA, Acquatella H, Rodriguez L, et al. Percutaneous edge-to edge mitral valve repair: 2-year follow-up in the first human case. Catheter Cardiovasc Interv. 2006;67:323–325. 25. Rogers JH, Franzen O. Percutaneous edge-to-edge MitraClip therapy in the management of mitral regurgitation. Eur Heart J. 2011;32:2350–2357. 26. Jilaihawi H, Hussaini A, Kar S. MitraClip: a novel percutaneous approach to mitral valve repair. J Zhejiang Univ Sci B. 2011;12:633–637. 27. Feldman T, Wasserman HS, Herrmann HC, et al. Percutaneous mitral valve repair using the edge-to-edge technique: six-month results of the EVEREST Phase I Clinical Trial. J Am Coll Cardiol. 2005;46:2134–2140. 28. Feldman T, Kar S, Rinaldi M, et al; EVEREST Investigators. Percutaneous mitral repair with the MitraClip system: safety and midterm durability in the initial EVEREST (Endovascular Valve Edge-to-Edge REpair Study) cohort. J Am Coll Cardiol. 2009;54:686–694. 29. Ussia GP, Barbanti M, Tamburino C. Feasibility of percutaneous transcatheter mitral valve repair with the MitraClip system using conscious sedation. Catheter Cardiovasc Interv. 2010;75:1137–1140. 30. Teufel T, Steinberg DH, Wunderlich N, et al. Percutaneous mitral valve repair with the MitraClip® system under deep sedation and local anaesthesia. EuroIntervention. 2012;8:587–590. 31. Maisano F, La Canna G, Latib A, et al. Transseptal access for MitraClip® procedures using surgical diathermy under echocardiographic guidance. J Am Coll Cardiol. 2008;52:1–142. 32. Silvestry FE, Rodriguez LL, Herrmann HC, et al. Echocardiographic guidance and assessment of percutaneous repair for mitral regurgitation with the Evalve MitraClip: lessons learned from EVEREST I. J Am Soc Echocardiogr. 2007;20:1131–1140. 33. Alegria-Barrero E, Chan PH, Paulo M, et al. Edge-to-edge percutaneous repair of severe mitral regurgitation–state-of-the-art for Mitraclip® implantation. Circ J. 2012;76:801–808. 34. Saitoh T, Izumo M, Furugen A, et al. Echocardiographic evaluation of iatrogenic atrial septal defect after catheter-based mitral valve clip insertion. Am J Cardiol. 2012;109:1787–1791. 35. Singh SM, Douglas PS, Reddy VY. The incidence and long-term clinical outcome of iatrogenic atrial septal defects secondary to transseptal catheterization with a 12F transseptal sheath. Circ Arrhythm Electrophysiol. 2011;4:166–171. 36. Rillig A, Meyerfeldt U, Kunze M, et al. Persistent iatrogenic atrial septal defect after a single-puncture, double-transseptal approach for pulmonary vein isolation using a remote robotic navigation system: results from a prospective study. Europace. 2010;12:331–336. 37. Bonow RO, Carabello BA, Chatterjee K, et al. 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2008;118:523–661. 38. Zoghbi WA, Enriquez-Sarano M, Foster E, et al; American Society of Echocardiography. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr. 2003;16:777–802. 39. Feldman T, Cilingiroglu M. Percutaneous leaflet repair and annuloplasty for mitral regurgitation. J Am Coll Cardiol. 2011;57:529–537. 40. Herrmann HC, Rohatgi S, Wasserman HS, et al. Mitral valve hemodynamic effects of percutaneous edge-to-edge repair with the MitraClip device for mitral regurgitation. Catheter Cardiovasc Interv. 2006;68:821–828. 41. Cockburn J, Fragkou P, Hildick-Smith D. Development of mitral stenosis after single MitraClip insertion for severe mitral regurgitation. Catheter Cardiovasc Interv. 2014;83:297–302. 42. Pope NH, Lim S, Ailawadi G. Late calcific mitral stenosis after MitraClip procedure in a dialysis-dependent patient. Ann Thorac Surg. 2013;95:e113–e114. 43. Mauri L, Garg P, Massaro JM, et al. The EVEREST II Trial: design and rationale for a randomized study of the evalve mitraclip system compared with mitral valve surgery for mitral regurgitation. Am Heart J. 2010;160:23–29. 44. Feldman T, Foster E, Glower DD, et al; EVEREST II Investigators. Percutaneous repair or surgery for mitral regurgitation. N Engl J Med. 2011;364:1395–1406. 45. Enriquez-Sarano M, Schaff HV, Frye RL. Mitral regurgitation: what causes the leakage is fundamental to the outcome of valve repair. Circulation. 2003;108:253–256. 46. Yuksel UC, Kapadia SR, Tuzcu EM. Percutaneous mitral repair: patient selection, results, and future directions. Curr Cardiol Rep. 2011;13:100–106.
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47. Grigioni F, Avierinos JF, Ling LH, et al. Atrial fibrillation complicating the course of degenerative mitral regurgitation: determinants and long-term outcome. J Am Coll Cardiol. 2002;40:84–92. 48. Grigioni F, Enriquez-Sarano M, Ling LH, et al. Sudden death in mitral regurgitation due to flail leaflet. J Am Coll Cardiol. 1999;34:2078–2085. 49. Lim E, Barlow CW, Hosseinpour AR, et al. Influence of atrial fibrillation on outcome following mitral valve repair. Circulation. 2001;104(12 suppl 1):I59–I63. 50. Chua YL, Schaff HV, Orszulak TA, et al. Outcome of mitral valve repair in patients with preoperative atrial fibrillation. Should the maze procedure be combined with mitral valvuloplasty? J Thorac Cardiovasc Surg. 1994;107:408–415. 51. Ngaage DL, Schaff HV, Mullany CJ, et al. Influence of preoperative atrial fibrillation on late results of mitral repair: is concomitant ablation justified? Ann Thorac Surg. 2007;84:434–442. 52. Suri RM, Schaff HV, Dearani JA, et al. Determinants of early decline in ejection fraction after surgical correction of mitral regurgitation. J Thorac Cardiovasc Surg. 2008;136:442–447. 53. Herrmann HC, Gertz ZM, Silvestry FE, et al. Effects of atrial fibrilla tion on treatment of mitral regurgitation in the EVEREST II (Endovascular Valve Edge-to-Edge Repair Study) randomized trial. J Am Coll Cardiol. 2012;59:1312–1319. 54. Whitlow PL, Feldman T, Pedersen WR, et al; EVEREST II Investigators. Acute and 12-month results with catheter-based mitral valve leaflet repair: the EVEREST II (Endovascular Valve Edge-to-Edge Repair) High Risk Study. J Am Coll Cardiol. 2012;59:130–139. 55. Mealing S, Feldman T, Eaton J, et al. EVEREST II high risk study based UK cost-effectiveness analysis of MitraClip® in patients with severe mitral regurgitation ineligible for conventional repair/replacement surgery. J Med Econ. 2013;16:1317–1326. 56. Maisano F, Godino C, Giacomini A, et al. Patient selection for MitraClip therapy impaired left ventricular systolic function. Minerva Cardioangiol. 2011;59:455–471. 57. Doebler K, Boukamp K, Mayer ED. Indication and structures and management of transcatheter aortic valve implantation: a review of the literature. Thorac Cardiovasc Surg. 2012;60:309–318. 58. Franzen O, Seiffert M, Baldus S, et al. Percutaneous mitral valve repair as a bail-out strategy for patients with severe mitral regurgitation after cardiac surgery. J Thorac Cardiovasc Surg. 2011;142:227–230. 59. Divchev D, Kische S, Paranskaya L, et al. In-hospital outcome of patients with severe mitral valve regurgitation classified as inoperable and treated with the MitraClip® device. J Interv Cardiol. 2012;25:180–189. 60. Boekstegers P, Hausleiter J, Baldus S, et al. Percutaneous interventional mitral regurgitation treatment using the Mitra-Clip system. Clin Res Cardiol. 2014;103:85–96.
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61. Available at: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/ medicaldevices/medicaldevicesadvisorycommittee/circulatorysystemdevices panel/ucm343684.pdf. Accessed February 20, 2014. 62. Leon MB, Smith CR, Mack M, et al; PARTNER Trial Investigators. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med. 2010;363:1597–1607. 63. Piérard LA, Carabello BA. Ischaemic mitral regurgitation: pathophysiology, outcomes and the conundrum of treatment. Eur Heart J. 2010;31:2996–3005. 64. Wu AH, Aaronson KD, Bolling SF, et al. Impact of mitral valve annuloplasty on mortality risk in patients with mitral regurgitation and left ventricular systolic dysfunction. J Am Coll Cardiol. 2005;45:381–387. 65. Franzen O, Baldus S, Rudolph V, et al. Acute outcomes of MitraClip therapy for mitral regurgitation in high-surgical-risk patients: emphasis on adverse valve morphology and severe left ventricular dysfunction. Eur Heart J. 2010;31:1373–1381. 66. Armstrong EJ, Rogers JH, Swan CH, et al. Echocardiographic predictors of single versus dual MitraClip device implantation and long-term reduction of mitral regurgitation after percutaneous repair. Catheter Cardiovasc Interv. 2013;82:673–679. 67. Maisano F, Franzen O, Baldus S, et al. Percutaneous mitral valve interventions in the real world: early and 1-year results from the ACCESS-EU, a prospective, multicenter, nonrandomized post-approval study of the MitraClip therapy in Europe. J Am Coll Cardiol. 2013;62:1052–1061. 68. Estévez-Loureiro R, Franzen O, Winter R, et al. Echocardiographic and clinical outcomes of central versus noncentral percutaneous edge-to-edge repair of degenerative mitral regurgitation. J Am Coll Cardiol. 2013;62:2370–2377. 69. Rogers JH, Low RI. Noncentral mitral regurgitation: a new niche for the MitraClip. J Am Coll Cardiol. 2013;62:2378–2381. 70. Grayburn PA, Foster E, Sangli C, et al. Relationship between the magnitude of reduction in mitral regurgitation severity and left ventricular and left atrial reverse remodeling after MitraClip therapy. Circulation. 2013;128:1667–1674. 71. Pleger ST, Chorianopoulos E, Krumsdorf U, et al. Percutaneous edge-to-edge repair of mitral regurgitation as a bail-out strategy in critically ill patients. J Invasive Cardiol. 2013;25:69–72. 72. Lim DS, Kunjummen BJ, Smalling R. Mitral valve repair with the MitraClip device after prior surgical mitral annuloplasty. Catheter Cardiovasc Interv. 2010;76:455–459. 73. Paranskaya L, D’Ancona G, Bozdag-Turan I, et al. Percutaneous mitral valve repair with the mitraclip((R)) system. Catheter Cardiovasc Interv. 2013;81:1224–1231. 74. Argenziano M, Skipper E, Heimansohn D, et al; EVEREST Investigators. Surgical revision after percutaneous mitral repair with the MitraClip device. Ann Thorac Surg. 2010;89:72–80. 75. Rogers JH, Yeo KK, Carroll JD, et al. Late surgical mitral valve repair after percutaneous repair with the MitraClip system. J Card Surg. 2009;24:677–681.
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Percutaneous Mitral Heart Valve Repair—MitraClip Jay V. Doshi, MD,* Sahil Agrawal, MD,† Jalaj Garg, MD,† Rajiv Paudel, MD,† Chandrasekar Palaniswamy, MD,† Tina V. Doshi, DO,‡ William Gotsis, MD,† and William H. Frishman, MD†
Abstract: Mitral regurgitation (MR) is the most common cardiac valvular disease in the United States. Approximately 4 million people have severe MR and roughly 250,000 new diagnoses of MR are made each year. Mitral valve surgery is the only treatment that prevents progression of heart failure and provides sustained symptomatic relief. Mitral valve repair is preferred over replacement for the treatment of MR because of freedom from anticoagulation, reduced long-term morbidity, reduced perioperative mortality, improved survival, and better preservation of left ventricular function compared with valve replacement. A large proportion of patients in need of valve repair or replacement do not undergo such procedures because of a perceived unacceptable perioperative risk. Percutaneous catheter-based methods for valvular pathology that parallel surgical principles for valve repair have been developed over the last few years and have been proposed as an alternate measure in high-risk patients. The MitraClip (Abbott Labs) device is one such therapy and is the subject of this review. Key Words: percutaneous mitral valve repair, MitraClip, mitral regurgitation (Cardiology in Review 2014;22: 289–296)
M
itral regurgitation (MR) is the most common cardiac valvular disease in the United States. Approximately 4 million people have severe MR and roughly 250,000 new diagnoses of MR are made each year.1,2 MR results from impaired systolic coaptation of the leaflets. Ischemic and nonischemic diseases cause regurgitation via functional and/or organic mechanisms. The valvular apparatus is largely preserved in the former and regurgitation occurs via multiple mechanisms, including left ventricular (LV) dilation, impaired LV wall motion, and papillary muscle dysfunction. The natural progression of MR is characterized by an increase in the regurgitant volume by 5–7 mL/year manifested by a progressive increase in effective regurgitant orifice and annular dilation.3 Patients with mild to moderate MR may remain asymptomatic for many years; however, patients with severe symptomatic MR have a 5% annual mortality without valve surgery.4 Medical therapy is a temporizing measure and has not been shown to improve survival.5 Its use is limited to symptomatic control in heart failure. Mitral valve (MV) surgery is the only treatment that prevents progression of heart failure and provides sustained symptomatic relief.6 MV repair is preferred over replacement for the treatment of MR because of freedom from anticoagulation, reduced long-term morbidity, reduced perioperative mortality, improved survival, and better preservation of LV function compared with valve
From the *Department of Cardiology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY; †Department of Medicine, Division of Cardiology, New York Medical College, Westchester Medical Center, Valhalla, NY; and ‡Department of Family Medicine, Nassau University Medical Center, East Meadow, NY. Disclosure: The authors have no conflicts of interest to report. Correspondence: Jalaj Garg, MD, 100 Woods Road, PMB 495, Valhalla, NY 10595. E-mail: [email protected]. Copyright © 2014 Lippincott Williams & Wilkins ISSN: 1061-5377/14/2206-0289 DOI: 10.1097/CRD.0000000000000036
replacement.7–9 A large proportion of patients in need of valve repair or replacement do not undergo such procedures because of a perceived unacceptable perioperative risk.10,11 Percutaneous catheterbased methods for valvular pathology that parallel surgical principles for valve repair have been developed over the last few years and have been proposed as an alternate measure in high-risk patients.12,13 The MitraClip (Abbott Labs, Abbott Park, IL) device is one such therapy and is the subject of this review.
HISTORICAL BACKGROUND The techniques for MV repair first introduced by Carpentier14 in the 1970s have since provided durable results in MR of varied etiology. The technique primarily involved quadrangular leaflet resection for those with prolapse, transposition of normal chords to other areas of prolapsing leaflet tissue if needed, and a remodeling annuloplasty with complete ring prosthesis. The annuloplasty improves repair durability in degenerative MR15; and in functional MR the annuloplasty itself generally constitutes the whole repair procedure. The Alfieri stitch or the edge-to-edge technique was introduced in the 1990s as a simpler alternative to correct MR.16 Suture approximation of the leading edges of the leaflets at the site of regurgitation can reduce its severity without causing inflow obstruction. This can be supplemented with a prosthetic ring to stabilize the repair. The simplicity, easy-reproducibility, and effectiveness of this technique led to utilization of the edge-to-edge repair in MR patients of different etiologies. Appropriate patient selection achieved by a reliable preoperative anatomic and functional assessment on echocardiography is essential. As the MitraClip device is an application of this concept, it is important to review results of outcomes with its surgical predecessor. A long-term follow up of 133 patients with segmental anterior leaflet prolapse treated with the edge-to-edge repair was reported in 2006. Ten-year survivals, freedom from cardiac death and freedom from reoperation were very satisfactory with only a small minority of patients in New York Heart Association (NYHA) functional classes III or IV upon a long-term follow up. Mitral stenosis did not occur at surgery or on follow up. Edge-to-edge repair provided similar satisfactory clinical and echocardiographic results in 115 patients with commissural prolapse.17 A 1.7% incidence of reoperation, and a 4.7% incidence of moderate or more severe MR was demonstrated on a mean follw up of 2.3 ± 1.9 years. The use of the edge-to-edge technique was a significant determinant of repair durability in patients with functional MR, increasing the freedom from recurrence of MR from 77 ± 12.1% to 95 ± 3.4% when used concomitantly with an undersized annuloplasty ring.18 Absence of annuloplasty is likely to be associated with accelerated failure of the repair resulting from increased stresses on the suture and the valve structure.16 It remains to be seen if this will make a difference when using the MitraClip (which does not involve a concomitant annuloplasty). As a bail-out procedure in 53 patients, the Alfieri stitch documented excellent immediate and long-term results.19 Smaller MV areas postprocedure do not translate into functional mitral stenosis either at baseline or during exercise.20 Current indications for edge-to-edge repair include segmental anterior leaflet flail/prolapse, bileaflet prolapse (facing segments), commissural prolapse/flail, functional MR and miscellaneous (systolic anterior motion, hypertrophic cardiomyopathy,
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complex congenital atrioventricular valve incompetence), and special situations (rescue, poor exposure, beating heart mitral repair, severe LV dysfunction, concomitant multiple procedures, transaortic approach). Contraindications to edge-to-edge repair include no localized regurgitant jet, rheumatic MR, small MV area, and multiple mitral lesions involving nonfacing segments of the anterior and posterior leaflets. This technique has been subsequently used in over 1000 patients with MR of various etiologies, and has demonstrated durable clinical outcome.21 The MitraClip device is a percutaneous extension of the Alfieri technique and mimics the surgical technique of edge-toedge repair by utilizing a catheter-delivered clip rather than a suture to create the double orifice in an attempt to reduce the regurgitation jet.22 The success of the technique was first demonstrated in a porcine model.23 The first implantation in a human was performed in 2003.24 The device was Conformité Européenne marked in March 200825,26 and is currently investigational in the United States, and available only through the Real world ExpAnded MuLtIcenter Study of the MitraClip System (REALISM) continued-access registry. Almost 4500 patients have undergone the procedure across the United States and Europe.
EQUIPMENT AND PROCEDURAL TECHNIQUE The MitraClip device and the procedural technique have been previously described in detail27,28 (Fig. 1 and 2). The MitraClip uses a tri-axial system consisting of a MitraClip device (implant), a clip delivery system (CDS) and a 24-F steerable guide catheter (Fig. 3). The clip is attached to the tip of the disposable delivery catheter that passes coaxially through the guide. The clip is made of 2 polyester covered cobalt chromium arms that are roughly 8 mm long and 4 mm wide and have a span of approximately 2 cm when open. On the inner aspect of each arm are U-shaped “barbs” or “grippers” that
FIGURE 1. Double-orifice surgical MV repair with suture. Illustration depicts a double-orifice mitral valve (MV) surgical repair. The MV is viewed from the left atrial side. The middle scallops of the anterior and posterior leaflets have been sutured together, which creates a double orifice, edge-to-edge, or bow tie repair. (Reprinted with permission from Feldman et al28). 290 | www.cardiologyinreview.com
help stabilize the leaflets when each leaflet is secured between the closed arm and the corresponding gripper. The clip can be opened, closed, locked, and detached by a control mechanism on the delivery catheter handle. The procedure is performed in a cardiac catheterization laboratory with echocardiographic and fluoroscopic guidance. The patient is placed under general anesthesia and mechanically ventilated. Ussia et al29 and Teufel et al30 have recently reported the successful implantation of the clip device under conscious sedation and local anesthesia. The femoral vein is cannulated and a right heart catheterization is performed to document right heart pressures. A transseptal puncture is then performed using a Brockenbrough needle. Transseptal puncture using surgical diathermy has been recently described in a series of 66 patients.31 This is a critically important point in the procedure and transesophageal echocardiography (TEE) is crucial to establish an ideal site. This is supplemented by fluoroscopy and transthoracic echocardiography. Four key TEE views are used to provide basic guidance.32 The bicaval and short axis views are used in combination with the “four”-chamber view. This is essential to ensure adequate height above the valve plane, especially in degenerative disease where the line of coaptation is above the annular plane. The ideal site is posterosuperior in degenerative and anteroinferior in functional MR, with the trajectory directed posteriorly.26 The transseptal puncture is ideally performed 3.5–4.0 cm above the line of coaptation of valvular leaflets. Intravenous heparin is administered at this point to maintain an activated clotting time of around 250 seconds. A 0.035inch stiff guide wire is then passed into the left atrium through the transseptal catheter and exchanged for the steerable guide catheter. An echo-bright and radio-opaque ring identifies the tip of the floating catheter. The CDS is then advanced through the guide catheter into the left atrial chamber under TEE guidance and the clip is cautiously centered over the origin of the MR jet, carefully avoiding the aorta and the atrial wall. The clip is then rotated to achieve a position perpendicular to the line of leaflet coaptation at the origin of the MR. After ensuring satisfactory orientation, the clip is lowered into the LV. The CDS is then pulled back with the clip arms in the grasping position until the leaflets are captured. The grippers are dropped and the clip is partially closed to secure the leaflet. An assessment of the adequacy of leaflet insertion is warranted at this time before assessing for reduction in MR. After confirming an adequate grasp, the degree of MR is assessed before the clip is incrementally closed and the degree of residual MR is assessed. If the leaflet attachment or the degree of MR reduction is not satisfactory, the leaflets are released, the clip is withdrawn and repositioned before a second attempt. If satisfactory reduction of MR is achieved, the clip is deployed and released from the CDS and final TEE images are obtained. Right heart catheterization is performed to document hemodynamic parameters. If MR reduction is inadequate, the device allows for disengagement of the clip prior to complete deployment. The results of the valve repair can therefore be assessed in real time and multiple sites can be tested for an optimal result. The guide catheter and CDS are then removed when results are deemed satisfactory. Groin hemostasis is achieved by manual compression, closure devices or suturing after the activated clotting time has decreased appropriately. After the procedure, preloading is achieved with aspirin (325 mg in the United States) and clopidogrel (300 mg if there was no prior treatment, followed by aspirin 81 mg) for 6 months and clopidogrel (75 mg) for 1 month.33 If the patient is under chronic anticoagulation, no additional treatment is required (continue with a target internationalized normal ratio of 2–3). Currently, device therapy is not an independent indication for anticoagulation. Whether this will translate to a higher rate of paradoxical embolic events in the presence of lower rates of closure of iatrogenic atrial septal defects remains to be seen.34–36 It is unclear if prophylaxis for infective endocarditis is warranted; however, some authors recommend such a practice.26 © 2014 Lippincott Williams & Wilkins
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FIGURE 2. The MitraClip device. The device is covered with polyester fabric to facilitate tissue in-growth. The distal gripping element helps with leaflet fixation. The clip delivery system exits through a guide catheter. (Reprinted with permission from Feldman et al28).
FIGURE 3. Patient selection criterion in EVEREST trial. The coaptation length must be at least 2 mm. Coaptation depth must be 25% and left ventricular systolic diameter ≤55 mm (3) Asymptomatic moderate-to-severe MR with LVEF 25–60% or left ventricular systolic diameter 40–50 mm or new onset atrial fibrillation (4) Pulmonary hypertension with pulmonary artery systolic pressure >50 mm at rest or >60 mm during exercise Exclusion criteria (1) Previous mediastinal surgeries (2) Mitral valve orifice area 48 hours, deep wound infection, septicemia, and new onset of atrial fibrillation (AF). Four-year follow up was complete in 161 patients (88%) in the device group and 73 patients (77%) in the surgical group. Sixty-eight patients (38.2%) received 2 devices during the index procedure. Nine patients were noted to have attachment of the device to a single leaflet during the first year with 1 additional incidence after 12 months. The rate of single leaflet attachment in practice is now closer to 1% compared with 5% in the trial. All these patients were treated with MV surgery (5 replacements and 5 repairs) with no device embolization. There was 1 postprocedural mitral stenosis at discharge (mean area, 1.5 cm and mean gradient, 14.5 mmHg). The patient eventually underwent MV replacement for recurrent MR 61 days after the original procedure. Five patients underwent an attempt to place a second MitraClip device through 12 months, with 4 of these being successful. Twenty-eight of 41 patients with initial unsuccessful percutaneous procedures and an additional 9 patients with an initially successful MitraClip but with late-onset device failure were referred to surgery. In the 12-month follow up, the outcomes of this subgroup were found to be similar to the original control group, thereby affirming that surgery is still viable and effective after a failed percutaneous procedure. The remaining patient underwent a successful implantation on an additional attempt between 12 months and © 2014 Lippincott Williams & Wilkins
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4 years of follow up. The primary safety end points at 12 months were observed in 9.6% and 57% in the device and control groups, respectively driven largely by a smaller need for blood transfusion which is expected with percutaneous therapy (8.8% vs 53.2% in the device and control groups, respectively, P < 0.0001). However, after adjusting for transfusion-related adverse events, the MitraClip still retained its superiority with regard to safety end points (0.7% vs 16.5%; P < 0.0001). An effective end point was reached in 39.8% in the percutaneous arm versus 53.4% in the surgical arm (P = 0.07). Similar rates of death (17.4% vs. 17.8%) and ≥3+ MR (21.7% vs. 24.7%) in the percutaneous repair and surgical groups were reported at 4 years of follow up. The rates of surgery for valvular dysfunction were 20.4% vs. 2.2% at 12 months and 24.8% vs. 5.5% over 4 years in the device versus surgical groups. However, the majority of surgical repairs after device therapy were encountered in the first year of follow up; and after the first year of follow up, there were similarly low rates of surgery required after either percutaneous or surgical treatment. This is in accordance with findings that the grade of MR generally remains stable beyond the first year of follow up. Surgical group patients experienced better MR reduction at discharge and at 4-year follow up than patients in the percutaneous repair group. Despite the more impressive improvements in MR grade with surgical repair, improvements in LV end-diastolic and end-systolic volumes of a similar magnitude were observed at 1 year and these were sustained at 4 years. Smaller LV end-diastolic diameters were noted in the surgical group at 4 years (4.84 ± 0.67 cm vs 5.25 ± 0.65 cm, P < 0.001). Similar improvements in NYHA functional class, as demonstrated by a decrease in the proportion of patients with class III or IV symptoms, were seen at 12 months and these improvements were persistent at 4 years. Functional MR is a greater operational challenge with surgical options that are more limited than for isolated leaflet pathology. Unlike degenerative MR, the relative benefit of surgery over medical therapy is less clear in MR of functional etiologies, and surgery is associated with more residual or recurrent MR.45 Sixty-six patients were found to have functional MR. Patients with functional MR experienced comparable effectiveness to surgery at 1 year and 4 years in exploratory analysis. Functional MR was more prevalent in the surgical arm in subjects with 3+ or 4+ MR at 4 years. In the EVEREST II trial, patients with MR of degenerative etiology derived greater benefit from surgery relative to percutaneous therapy compared with patients with functional MR. There is a trend for percutaneous therapy to be selected for patients with either functional MR outside of the US experience.46 The potential benefits of percutaneous MV replacement over surgical repair demonstrated in the study were (1) the reduction in MR was similar between the 2 interventions and (2) the reductions in MR grade and LV end-diastolic volume were significantly reduced with surgery compared to percutaneous MV replacement, but patients treated with percutaneous MV replacement demonstrated significantly reduced LV end-diastolic parameters with improvement in NYHA class and quality of life.44
Effects of Atrial Fibrillation in EVEREST II Trial MV surgery is a class IIa indication in patients with severe MR with new onset AF. AF which develops at a rate of approximately 5%1 in patients with MR portends a worse prognosis47,48 Varying rates of success have been noted in surgical series of patients with AF who undergo valve replacement or repair with similar49,50 or worse results51,52 demonstrated in different studies. Herrmann et al53 assessed the impact of AF on the outcomes of both the MitraClip procedure and surgical repair in a posthoc analysis of the EVEREST II trial. Of 264 patients, 72 had AF on the basis of their baseline © 2014 Lippincott Williams & Wilkins
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rhythm. Of these, 45 underwent percutaneous therapy with the MitraClip device. Patients with AF were older, had more medical comorbidities, a lower LVEF, and higher prevalence of NYHA classes III–IV symptoms. Functional MR (40% vs 19%) was more likely, however, MR grades were similar. Despite a seemingly more difficult procedure in the presence of an irregular rhythm, reduction of MR to ≤2+ was equally successful in patients with and without AF (83% vs 75%). Device attachment to a single leaflet occurred in 13% of AF patients versus 3% of non-AF patients. Freedom from death, MV surgery for valve dysfunction, and MR >2+, was similar for AF patients (64%), and non-AF patients (61%). A similar reduction in MR grade (to ≤2+) at discharge occurred in AF patients (97%) verus non-AF patients (85%). Freedom from all-cause mortality at 1 year did not differ by rhythm. Therefore, patients with MR and AF can expect similar benefits as their non-AF counterparts, and if found to meet clinical and echocardiography criteria, should be offered this therapy independent of the presenting rhythm. A greater difficulty in assessing leaflet insertion during echocardiography and additional caution to ensure leaflet insertion before clip release is, however, warranted.
EVEREST II High-Risk Registry All patients with elevated surgical risk secondary to comorbidities or previous cardiac surgeries were included in the EVEREST II high-risk analysis.54 The study population consisted of 78 high-risk patients with a predicted mortality of ≥12% [measured by the Society of Thoracic Surgery (STS) calculator]. All patients with LVEF ≤20%, unfavorable MV anatomy, LV end-systolic diameter >60 mm, and MVe area 4 cm2 and adequate leaflets tissue for mechanical coaptation. There are no clear indication criteria for the use of the MitraClip System (MCS), however, literature suggests (1) patients with symptomatic/ asymptomatic MR 3+ or 4+ with reduced LVEF, (2) multimorbidity, high-risk patient, contraindication for open MV surgery, log EuroSCORE >20% and/or STS score >12%, (3) AHA/ACC criteria for open MV valve surgery fulfilled, and (4) porcelain aorta or postradiation mediastinum.56–58 Possible indications for the use of MCS (1) symptomatic or asymptomatic MR 3+ or 4+ with normal LVEF and (2) younger patients (60 mm, transient ischemic attack or stroke within last 6 months, and myocardial infarction within last 3 months are ineligible for the procedure. If leaflet tethering is determined on echocardiogram, then coaptation depth >11 mm or vertical length 12% or patients deemed to be high risk for operation by surgeons by meeting ≥1 of prespecified criteria. Two major shortcomings were noted, however. Less than 62% patients were actually seen by surgeons before being included in the too high-risk group and 60% of the patients in these cohorts might not have been completely inoperable.61 Arguments were also made against pooling data from the 2 registries as they were conducted a year apart with subsequent differences in operator experience thereby possible.61 The 2 registries may have actually had patients with different risk categories given that major differences were noted between baseline characteristics (mean EF, MR etiology, and STS predicted risk). However, after entertaining these specific caveats, the panel agreed that this should not prevent premarket approval support for the intended population. A stricter criterion of MR ≤1+ at discharge as opposed to ≤2+ was suggested to be used for assessing effectiveness in EVEREST II by the FDA. A similar outcome was demonstrated when the pooled data from the high-risk registries were compared with data from the MCS-treated EVEREST II patients based on this new criterion. A deficiency of data on quality of life and use of heart failure medications remains and the limitation associated with interpreting the effectiveness in the absence of a suitable comparator must be acknowledged. A randomized-controlled trial similar to the Placement of Aortic Transcatheter Valves (PARTNER) trial would have been ideal to compare the merit of the device in this population that is too high risk for surgery.62 In summary, EVEREST II was unable to provide reasonable safety and effectiveness data in support of using the MCS in patients eligible for both therapies; and the ability of the single arm, high-risk registries to provide reliable and adequate data on too high-risk patients was found to be limited. The need for a palliative alternative for surgical high-risk patients was considered for the final risk/benefit vote. The MCS received FDA approval in October 2013 and is intended to treat patients with significant symptomatic degenerative MR with MR ≥3+ who have too high risk for surgery. 294 | www.cardiologyinreview.com
FUTURE DIRECTIONS While MV repair is an established treatment for degenerative MR, its role in the management of functional MR is unclear.63 The EVEREST trials investigated the new therapy in patients largely with degenerative MR. Surgical repair for functional MR currently has a IIb recommendation according to the AHA/ACC and European guidelines,64 Franzen et al65 demonstrated the feasibility of the MitraClip device in patients with severe LV dysfunction (EF ≤ 25%) and significant functional MR with a high logistic EuroSCORE. This was an important cohort of patients, as surgery has not been shown to have a survival benefit in this group with end stage heart failure.64 Their findings of a higher rate of MR reduction than the EVEREST cohort supports the hypothesis that percutaneous therapy might be more successful in treating functional MR. This finding is probably not surprising as functional MR patients usually have structurally normal thickness of their leaflets, etc., which probably makes it easier to grab the leaflets as compared to the degenerated leaflets of organic MR patients where it may be challenging. The acute reduction in MR severity was accompanied by sustained improvements in objective measures of symptom control and LV remodeling. Rates of 30-day mortality and 6-month survival similar to surgery and resynchronization therapy, respectively were also demonstrated. A European study expanded the use of the clip on an experimental basis to high surgical risk patients, 70% of whom would have been excluded in the original EVEREST trial either because of LV dysfunction or valve anatomy.66 The therapy was feasible in this cohort without major adverse events. As experience with the device increases, the possibilities of utilization of this percutaneous therapy continue to expand.67–70 Pleger et al71 successfully utilized device therapy as a tool for acute stabilization of high-risk patients who could subsequently be weaned off inotropic/ventilator therapy in the days following percutaneous valve repair. More recently, the MitraClip was successfully used as a less invasive option for prior failed annuloplasty instead of a higher risk reoperation for MR.72 The goal of surgery for MR is resolution of the regurgitation. The EVEREST trial did not aim for this and instead defined acute procedural success as reduction of MR to ≤2+. Paranskaya et al73 found that elimination rather than reduction of MR to ≤2+ resulted in better mortality outcomes. In addition to being safe and efficacious, a new percutaneous technique should not impede the safety or success of conventional surgery in the event of initial treatment failure. Argenziano et al74 reported that surgical options were largely preserved and successful repair was equally feasible as late as 18 months after clip implantation. Thirty-two patients enrolled in the EVEREST I and II trials underwent MV repair or replacement for various reasons after MitraClip therapy: 84% of planned repairs were successful; 11 patients had some degree of valve damage as a result of the procedure or clip removal. MV repair or replacement was performed as planned in all but 4 patients. Only 1 of these 4 patients had a replacement that was directly related to damage caused by the MitraClip procedure. These surgeries resulted in MR grade ≤2+ in all patients. Rogers et al75 reported successful surgical MV repair in a series of 4 patients up to 5 years after MitraClip implantation, therefore very late MV repair remains possible. It must be anticipated that an increasing number of percutaneous MV replacement procedures will be performed in the near future and more cases after failed intervention will occur. Therefore, surgical strategies may need to be adapted to this situation.
CONCLUSIONS Although limited clinical data have provided promising results for MitraClip implantation in the EVEREST trial irrespective of the etiology of MR, large randomized double-blind trials are needed to establish its clinical applicability. © 2014 Lippincott Williams & Wilkins
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