NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE

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1 NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE INTERVENTIONAL PROCEDURES PROGRAMME Interventional procedure overview of percutaneous mitral valve leaflet repair for mitral regurgitation Mitral regurgitation occurs when the mitral valve does not close properly, allowing blood to leak backwards. This can lead to shortness of breath and the heart may be unable to pump enough blood to the rest of the body. During percutaneous mitral valve leaflet repair, a catheter is inserted into the skin, through the femoral vein and passed through to the heart. The two leaflets of the mitral valve are partially clipped or sewn together to reduce the amount of blood leaking backwards. Introduction The National Institute for Health and Clinical Excellence (NICE) has prepared this overview to help members of the Interventional Procedures Advisory Committee (IPAC) make recommendations about the safety and efficacy of an interventional procedure. It is based on a rapid review of the medical literature and specialist opinion. It should not be regarded as a definitive assessment of the procedure. Date prepared This overview was prepared in October Procedure name Percutaneous mitral valve leaflet repair Specialty societies British Cardiovascular Intervention Society Society of Cardiothoracic Surgeons of Great Britain and Ireland Page 1 of 16

2 Description Indications and current treatment Mitral regurgitation is characterised by backward flow of blood from the left ventricle to the left atrium during systole. It may cause the left ventricle to become enlarged and weakened because of the additional workload required to maintain normal forward blood flow. Left untreated, moderate to severe mitral regurgitation can cause congestive heart failure and eventually lead to death. Mitral regurgitation may be caused by a variety of mechanisms involving abnormalities of the valve leaflets, the sub-valvar support apparatus, and the mitral valve annulus. Most often it is caused by a combination of pathologies resulting from degenerative leaflet disease, rheumatic disease and annular dilation as a result of dilated or ischaemic cardiomyopathy. Mild and moderate mitral regurgitation are often managed conservatively. More severe mitral regurgitation may require surgical valve repair (for example, through partial leaflet resection, annuloplasty, chordal repair or a combination of these) or valve replacement, using either an open surgical or thoracoscopic approach. The severity of mitral regurgitation is graded using echocardiography on a scale from 1 to 4: grade 1 is mild, grade 2 is moderate, grade 3 is moderate to severe and grade 4 is severe. What the procedure involves The aim of percutaneous mitral valve leaflet repair is to create a double orifice mitral valve during diastole and keep the leaflets more closely apposed during systole, thereby reducing the amount of regurgitation. With the patient under general anaesthesia, a catheter is advanced through the femoral vein into the right atrium and then into the left atrium via a transseptal puncture using fluoroscopy and transoesophageal guidance. Subsequent technique details may vary according to the type of device used, but all techniques involve partial clipping or suturing of the mitral leaflets to each other at the point of origin of the regurgitant jet. Transoesophageal echocardiography and/or fluoroscopy can be used to assess whether mitral regurgitation has been adequately reduced and the clip or suture may be repositioned as necessary. List of studies included in the overview This overview is based on 188 patients from one multicentre case series (reported in four different publications) and an additional case report. All studies reported outcomes after percutaneous mitral valve leaflet repair using a clip device rather than with suturing. Page 2 of 16

3 Efficacy A case report of the first human case of percutaneous mitral valve leaflet repair described a successful procedure in which mitral regurgitation was reduced from grade 4 pre-operatively to grade 1 at 1- and 2-year follow-up. The patient had exertional dyspnoea which resolved within 30 days of the procedure and she remained asymptomatic at the 2-year follow-up 1. In a multicentre case series of 47 patients, the procedure was successful in 34 patients (72%). Procedural success was defined as clip placement with reduction in mitral regurgitation to grade 2 or less as measured by core laboratory echocardiographic assessments at hospital discharge. In 5 patients the clip was not left in place because of insufficient reduction in mitral regurgitation 2. Of the 107 patients who were involved in phases I and II of the multicentre case series, clip placement was successful in 90% (96/107) of patients 3. Acute procedural success (defined as patients receiving a clip implant with reduction of MR to grade 2+ or less, based on the American Society of Echocardiography guidelines) was achieved in 74% (79/107) of patients. Of the 79 patients who had acute procedural success, mitral regurgitation was maintained at grade 2+ or lower in 77% of patients at discharge (absolute figures not reported) and 66% (50/76) of patients at 12-month follow-up (measured by core laboratory echocardiographic assessments) 3. The composite primary efficacy endpoint (defined as freedom from MR > grade 2+, freedom from surgery for valve dysfunction, and freedom from death for per-protocol population, at 12-month follow-up) was achieved in 66% of patients (absolute numbers not reported) 3. In the first 27 patients in the trial, mean mitral valve gradient increased from 1.79 mmhg at baseline to 3.31 mmhg immediately after clip deployment (p = 0.004, n = 16) and 3.56 mmhg at 12-month follow-up (n = 13). Mitral valve area (measured by planimetry) decreased from 6.49 cm 2 at baseline to 4.46 cm 2 after clip deployment (p < 0.001, n = 18) and 3.79 cm 2 at 12-month follow-up (n = 13) 4. In total (of the first 27 patients in the phase I study), 6 patients required surgical revision after the procedure (mean 56 ± 55 days after percutaneous mitral valve leaflet repair; range days) for recurrent or persistent mitral regurgitation because of malpositioning of the clip at the time of implantation (n = 4) causing partial clip detachment in 3 patients, and insufficient mitral regurgitation reduction at the time of implantation (n = 2) 5. Safety In 107 patients in phases I and II of the multicentre case series, 10 patients had a major adverse event within 30 days. Partial clip detachment (from one or two leaflets) occurred in 9% (10/107) of patients 3. No perioperative Page 3 of 16

4 mortality was reported. One patient had a non-embolic stroke with neurological deficit lasting 72 hours, but this resolved within 30 days. Bleeding requiring blood transfusion occurred in 4% (4/107) of patients. Literature review Rapid review of literature The medical literature was searched to identify studies and reviews relevant to percutaneous mitral valve leaflet repair. Searches were conducted of the following databases, covering the period from their commencement to 13/08/2008, and updated to 04/03/2009: MEDLINE, PREMEDLINE, EMBASE, Cochrane Library and other databases. Trial registries and the Internet were also searched. No language restriction was applied to the searches (see appendix C for details of search strategy). The following selection criteria (table 1) were applied to the abstracts identified by the literature search. Where selection criteria could not be determined from the abstracts the full paper was retrieved. Table 1 Inclusion criteria for identification of relevant studies Characteristic Publication type Patient Intervention/test Outcome Language Criteria Clinical studies were included. Emphasis was placed on identifying good quality studies. Abstracts were excluded where no clinical outcomes were reported, or where the paper was a review, editorial, or a laboratory or animal study. Conference abstracts were also excluded because of the difficulty of appraising study methodology, unless they reported specific adverse events that were not available in the published literature. Patients with mitral regurgitation. Percutaneous mitral valve leaflet repair. Articles were retrieved if the abstract contained information relevant to the safety and/or efficacy. Non-English-language articles were excluded unless they were thought to add substantively to the English-language evidence base. Existing assessments of this procedure There were no published assessments from other organisations identified at the time of the literature search. Related NICE guidance Below is a list of NICE guidance related to this procedure. Appendix B gives details of the recommendations made in each piece of guidance listed. Page 4 of 16

5 Interventional procedures Thoracoscopically assisted mitral valve surgery. NICE interventional procedures guidance 245 (2007). Available from Page 5 of 16

6 Table 2 Summary of key efficacy and safety findings on percutaneous mitral valve leaflet repair Abbreviations used: EVEREST, Endovascular Valve Edge-to-Edge Repair Study; MR, mitral regurgitation; MV, mitral valve; NYHA, New York Heart Association Study details Key efficacy findings Key safety findings Comments Silvestry (2007) 2 Study type: multicentre case series (phase I trial) Country: USA Study period: not stated Study population: patients with moderate to severe (grade 3) or severe (grade 4) MR Aetiology: degenerative disease of the MV (87%), functional or ischaemic MR (13%) n = 47 Mean age: 67 years (±12 years) Sex: not stated Inclusion criteria: Met American Heart Association criteria for MV repair. Transthoracic and transoesophageal echocardiograms showing at least three of the six American Society of Echocardiography criteria for moderate to severe or severe MR. Procedural success 72% (34/47) of patients had a successful procedure (defined as placement of a clip with echocardiographic core laboratory reduction in MR at discharge to at least grade 2+). In 5 patients, the clip was not left in place due to insufficient MR reduction (3 patients were enrolled before placement of a second clip was allowed in the protocol). None of these 5 patients had major adverse events and all had elective surgery: 4 had repair procedures and 1 had mitral valve replacement as intended. Complications 2 patients had surgery before discharge: 1 for delivery catheter malfunction and the other because of partial clip detachment. These patients were part of EVEREST a multicentre phase I safety and feasibility trial of the Mitraclip device. The stated study objective was to assess the impact of a standardised echocardiographic protocol for the guidance of the procedure (for example, on reducing procedure time). Mitral regurgitation grading: grade 1: mild grade 2: moderate grade 3: moderate to severe grade 4: severe. Technique: percutaneous MV leaflet repair using the Mitraclip device (Evalve Inc., California). Follow-up: 12 months Conflict of interest: study was part funded by the manufacturer Page 6 of 16

7 Abbreviations used: EVEREST, Endovascular Valve Edge-to-Edge Repair Study; MR, mitral regurgitation; MV, mitral valve; NYHA, New York Heart Association Study details Key efficacy findings Key safety findings Comments Feldman (2009) 3 Study type: multicentre case series (phase I / II trial) Country: USA Study period: not stated Study population: patients with moderate-to-severe (grade 3) or severe (grade 4) MR Aetiology: degenerative disease of the MV (93%), functional or ischaemic MR (7%) n = 107 Mean age: 71 years (median) Sex: 62% male Comorbidities: history of congestive heart failure (59%), NYHA class III or IV (44%), atrial fibrillation (41%) Inclusion criteria: Symptomatic or if asymptomatic: Left ventricular ejection fraction < 60% or Left ventricular end-systolic dimension > 45 mm Technique: percutaneous MV leaflet repair using the Mitraclip device (Evalve Inc., California) Technical success of procedure Clip implantation achieved in 90% (96/107) of patients. Unsuccessful clip implantation in 10% (11/107) of patients. Acute procedural success (defined as patients receiving a clip implant with reduction of MR to grade 2+ or less) was achieved in 74% (79/107) of patients. MR severity Of the 79 patients who were rated as acute procedural success: Discharge 12 months Grade 2+ 77% 66% (50/76) Not assessed not reported 3 Composite primary efficacy endpoint Defined as freedom from MR > grade 2+, freedom from surgery for valve dysfunction, and freedom from death for per-protocol population, at 12-month follow-up. Primary efficacy endpoint was achieved in 66% of patients (absolute numbers not reported) Heart function Baseline 12 months NYHA grade I or II 45% (29/65) 92% (60/65) NYHA grade III or IV 55% (36/65) 8% (5/65) (measurement of significance not reported) In-hospital complications No procedural mortality. Bleeding requiring blood transfusion 4% (4/107). Mechanical ventilation > 48 hours 2% (2/107). There were no cases of renal failure or dialysis. Primary safety endpoint 10 patients had experienced a major adverse event at 30-day follow-up (including one death in a patient in whom no clip was placed and MR not reduced). 1 patient with a history of TIA had a non embolic stroke with neurological deficit >72 hours, but resolved at 30 days. 9% (10/107) of patients had partial clip detachment from one of the two valve leaflets: 3 patients during the procedure, 1 before hospital discharge, 5 before 30-day followup and 1 after 30-day follow-up. None of the partial clip detachments required urgent surgical intervention These patients were part of EVEREST I and II a multicentre safety and feasibility trial of the Mitraclip device. These patients are likely to be the same as those in the study by Silvestry et al. (2007). 31 participating sites. 70% of the patients treated are the 1 st 2 nd or 3 rd operated on at each institution. Patients who did not receive a clip or underwent subsequent MV surgery were not followed up. Follow-up: up to 3 years Conflict of interest: supported by manufacturer Page 7 of 16

8 Abbreviations used: EVEREST, Endovascular Valve Edge-to-Edge Repair Study; MR, mitral regurgitation; MV, mitral valve; NYHA, New York Heart Association; Study details Key efficacy findings Key safety findings Comments Herrmann (2006) 4 Study type: multicentre case series (phase I trial) Country: USA Study period: not stated Study population: patients with moderate to severe (grade 3) or severe (grade 4) MR Aetiology: degenerative disease of the MV (93%), functional or ischaemic MR (7%) n = 27 Mean age: 69 years (±13 years) Sex: 59% male Comorbidities: history of congestive heart failure (59%), NYHA class III or IV (44%), atrial fibrillation (41%) Inclusion criteria: Symptomatic or if asymptomatic: Left ventricular ejection fraction < 60% or Left ventricular end-systolic dimension > 45 mm Technique: percutaneous MV leaflet repair using the Mitraclip device (Evalve Inc., California) Follow-up: 12 months Conflict of interest: none stated In 3 patients, no clip was placed (no further information stated); 6 patients had their clips explanted by 6 months (range days, none for mitral stenosis; no further information stated); 4 patients received two clips ( in 1 patient the first clip was not optimally placed and surgery was performed within 30 days ). Mitral valve area and gradient before discharge from hospital Haemodynamic outcomes were assessed immediately after the procedure and echocardiographic outcomes were assessed on the day of hospital discharge (mean 1.8 days postoperatively). Preoperative Postoperative p-value Mean MV gradient by Doppler (mmhg) 1.79 ± ± (n = 16) Mean MV gradient by haemodynamics 5.00 ± ± (mmhg) (n = 8) Peak MV gradient by Doppler (mmhg) 6.26 ± ± (n = 18) MV area by planimetry (cm 2 ) (n = 18) 6.49 ± ± MV area by pressure half-time (cm 2 ) 4.35 ± ± (n = 7) MV area by Gorlin formula (cm 2 ) (n = 8) 2.78 ± ± Mitral valve area and gradient at 12-month follow-up Discharge 12 months p-value Mean MV gradient by Doppler (mmhg) (n = 13) 3.22 ± ± Peak MV gradient by Doppler (mmhg) (n = 12) 5.92 ± ± MV area by planimetry (cm 2 ) (n = 13) 3.90 ± ± MV area by pressure half-time (cm 2 ) (n = 5) 4.60 ± ± Other There was a significant reduction in MR in 14 patients, which lasted up to at least 1 year in 13 patients. No safety outcomes were reported in this publication (see study by Feldman et al. 2005) These patients were part of EVEREST a multicentre phase I safety and feasibility trial of the Mitraclip device. These patients are the same as those included in the study by Feldman et al. (2005). Page 8 of 16

9 Abbreviations used: EVEREST, Endovascular Valve Edge-to-Edge Repair Study; MR, mitral regurgitation; MV, mitral valve; NYHA, New York Heart Association Study details Key efficacy findings Key safety findings Comments Dang (2005) 5 Study type: case series Country: USA Study period: not stated Study population: patients from three centres with MR after percutaneous clip deployment for MV repair and who later required surgical intervention. The patients were part of a group of 27 patients enrolled in a phase I clinical trial of the Mitraclip device. n = 6 Technique: percutaneous edge-to-edge repair using the Mitraclip device (Evalve Inc., California) Mean follow-up: 55 days Conflict of interest: six authors disclosed a financial relationship with the manufacturer Complications The 6 patients required subsequent surgical intervention (55.5 ± 55 days later, range days) for recurrent or persistent MR. Four patients had malpositioning of the clip at the time of implantation (in 3 patients the clip partially detached from either the anterior or posterior leaflets). Two patients had insufficient MR reduction at the time of implantation (in 1 patient the clip was placed suboptimally and could not be repositioned due to a malfunction of the delivery catheter). Outcome of surgical revision In all patients, the clip was removed from the leaflets without difficulty. Five patients required MV repair and 1 patient underwent MV replacement. Five patients recovered well without any complications and reported an improvement in symptoms. One patient developed a right-sided ilio-femoral deep venous thrombosis on the same side as the catheter insertion site 3 days after the surgical intervention and 4 days after the percutaneous procedure. The patient was maintained on anticoagulation therapy. The patient also developed a symptomatic pericardial effusion that required percutaneous pericardiocentesis. Mean MR grade Before percutaneous leaflet repair: 3.7 (±0.5). Immediately after percutaneous leaflet repair: 1.8 (±1.0). Before surgical revision: 3.2 (±0.8). After surgical revision: 0.7 (±0.8). These patients were part of EVEREST a multicentre phase I safety and feasibility trial of the Mitraclip device. These patients are the same as those included in the studies by Feldman et al. (2005) and Herrmann et al. (2006). Page 9 of 16

10 Abbreviations used: EVEREST, Endovascular Valve Edge-to-Edge Repair Study; MR, mitral regurgitation; NYHA, New York Heart Association Study details Key efficacy findings Key safety findings Comments Condado (2006) 1 Study type: case series Country: Venezuela Study period: June 2003 Study population: a 49-year old woman with severe MR (grade 4) secondary to bi-leaflet prolapse and anterior mitral leaflet flail (presented with worsening exertional dyspnoea) n = 1 Echocardiography immediately after the procedure and 24 hours later showed the clip was well placed. Exertional dyspnoea resolved within 30 days of the procedure and the patient remained asymptomatic with mild MR 2 years after the procedure (MR reduced from grade 4 preoperatively to grade 1 at 1- and 2-year follow-up). Complications There were no complications reported. Technique: percutaneous edge-to-edge repair using the Mitraclip device (Evalve Inc., California) Follow-up: 2 years Conflict of interest: two authors received support from or had equity in the manufacturer Page 10 of 16

11 Validity and generalisability of the studies The overview is based on 48 patients in total, of whom 47 took part in a manufacturer-sponsored trial of a mitral valve clip device. There was no published evidence on the suturing technique for percutaneous mitral valve leaflet repair. Specialist Advisers opinions Specialist advice was sought from consultants who have been nominated or ratified by their Specialist Society or Royal College. The advice received is their individual opinion and does not represent the view of the society. Michael O Sullivan (British Cardiovascular Intervention Society), Francis Wells (Society of Cardiothoracic Surgeons of Great Britain and Ireland). Both Specialist Advisers thought it was a novel procedure (or the first in a new class of procedures) and that the comparator would be open mitral valve repair. Both Advisers had never performed this procedure. Safety Specialist Advisers thought that theoretical adverse events included: leaflet tearing, clip embolism, partial clip detachment, return of mitral regurgitation, complications from vascular access, cardiac tamponade from attempted transseptal puncture and scar formation around the clip causing effective mitral stenosis and obstructing the mitral valve orifice. Efficacy Specialist Advisers thought that key efficacy outcomes included: successful clip delivery, reduction of mitral regurgitation, durability, left ventricular dimensions and function, need for subsequent mitral valve surgery and quality of life. Specialist Advisers stated that there was uncertainty about the procedure s efficacy in the short- and long-term. One Adviser stated that it should only be used in the context of clinical trials. Issues for consideration by IPAC Long-term echocardiographic follow-up (longer than 1 year) is needed to assess residual mitral regurgitation. Is the current title appropriate? Consider mitral valve leaflet apposition for mitral regurgitation. Page 11 of 16

12 References 1. Condado JA, Acquatella H, Rodriguez L et al. (2006) Percutaneous edgeto-edge mitral valve repair: 2-year follow-up in the first human case. Catheterization and Cardiovascular Interventions 67: Silvestry FE, Rodriguez LL, Herrmann HC et al. (2007) Echocardiographic guidance and assessment of percutaneous repair for mitral regurgitation with the Evalve MitraClip: lessons learned from EVEREST I. Journal of the American Society of Echocardiography 20: Feldman T, Kar S, Rinaldi M et al. (2009) Percutaneous mitral repair with the MitraClip System: Safety and Midterm Durability in the initial EVEREST cohort. Journal of the American College of Cardiology 54: Herrmann HC, Rohatgi S, Wasserman HS et al. (2006) Mitral valve hemodynamic effects of percutaneous edge-to-edge repair with the MitraClip device for mitral regurgitation. Catheterization and Cardiovascular Interventions 68: Dang NC, Aboodi MS, Sakaguchi T et al. (2005) Surgical revision after percutaneous mitral valve repair with a clip: initial multicenter experience. Annals of Thoracic Surgery 80: Page 12 of 16

13 Appendix A: Additional papers on percutaneous mitral valve leaflet repair There were no additional papers identified. Page 13 of 16

14 Appendix B: Related NICE guidance for percutaneous mitral valve leaflet repair Guidance Interventional procedures Recommendations Thoracoscopically assisted mitral valve surgery. NICE interventional procedures guidance 245 (2007) Evidence from large case series supports the safety and efficacy of thoracoscopically assisted mitral valve surgery. Therefore, clinicians wishing to use this procedure should do so with normal arrangements for clinical governance and consent Thoracoscopically assisted mitral valve surgery is technically demanding. Surgeons undertaking it should have special expertise and specific training in thoracoscopic cardiac surgery, and should perform their initial procedures with an experienced mentor. Page 14 of 16

15 Appendix C: Literature search for percutaneous mitral valve leaflet repair Database Date searched Version searched Cochrane Database of Systematic Reviews CDSR (Cochrane Library) Database of Abstracts of Reviews of Effects DARE (CRD website) 08/08/2008 Issue 3, /08/ HTA database (CRD website) 08/08/ Cochrane Central Database of Controlled Trials CENTRAL (Cochrane Library) 08/08/2008 Issue 3, MEDLINE (Ovid) 07/08/ to July 179 Week MEDLINE In-Process (Ovid) 07/08/ EMBASE (Ovid) 07/08/ to Week CINAHL (NLH Search 2.0) 08/08/ to present 22 BLIC (Dialog DataStar) 11/08/ National Research Register (NRR) 11/08/ Archive UK Clinical Research Network 11/08/ (UKCRN) Portfolio Database Current Controlled Trials metaregister of Controlled Trials - mrct 11/08/ Clinicaltrials.gov 11/08/ No. retrieved The following search strategy was used to identify papers in MEDLINE. A similar strategy was used to identify papers in other databases. 1 Surgical Procedures, Minimally Invasive/ 2 percutan$.tw. 3 endovascular$.tw. 4 or/1-3 5 Mitral Valve/ 6 Heart Valves/ 7 (mitral adj3 valve$).tw. 8 (heart adj3 valve$).tw. Page 15 of 16

16 9 (bicuspid adj3 valve$).tw. 10 (cardiac adj3 valve$).tw. 11 or/ (repair$ or reconstruc$ or clos$).tw and Mitral Valve Insufficiency/ 15 (Mitral adj3 insufficien$).tw. 16 (Mitral adj3 regurgitat$).tw. 17 (mitral adj3 incompet$).tw. 18 or/ and 13 and Mitraclip.tw or 20 Page 16 of 16