National Institute for Health and Clinical Excellence

IP 664

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 through the skin via a large vein in the groin or neck 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 of 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 2008. Procedure name

• Percutaneous mitral valve leaflet repair

Specialty societies

• British Cardiovascular Intervention Society • Society of Cardiothoracic Surgeons of Great Britain and Ireland

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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 47 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.

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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-up1.

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 regurgitation2.

Of the 27 patients who were involved in the phase I stage of the study, the procedure was successful in 22 (81%) and these patients were discharged from hospital with a clip in place. In 5 patients the procedure was unsuccessful: in 3 patients the clip was not left in place; in 1 patient there was partial clip detachment within 24 hours; and in 1 patient there was inadequate mitral regurgitation reduction (although this was apparent during the procedure, it was not possible to re-open and remove the clip because of device malfunction, so it was left in place). All 5 patients who had unsuccessful procedures had subsequent elective surgical mitral valve repair3.

Of the 22 patients who had successful clip insertion, mitral regurgitation was reduced to grade 2 or lower in 14 (64%) at 30-day follow-up (measured by core laboratory echocardiographic assessments) and this improvement was maintained in 13 patients at 6-month follow-up. At 30-day and 6-month follow- up, mitral regurgitation of grade 3 or greater was measured in 6 (27%) and 4 (18%) patients, respectively. Two patients had mitral regurgitation recurrence and another 2 patients had partial clip detachment at a 30-day follow-up assessment3.

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 cm2 at baseline to 4.46 cm2 after clip deployment (p < 0.001, n = 18) and 3.79 cm2 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 1-133 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.

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Safety

In the first 27 patients in the trial, 4 (15%) had a major adverse event within 30 days. Clip detachment from one of the two valve leaflets occurred in 3 patients (one was diagnosed during the 24-hour echocardiogram and two were diagnosed at 30-day follow-up). One patient had a permanent non-embolic stroke associated with postoperative hypotension. The only in-hospital complication was that 1 patient needed a blood product transfusion during the procedure3.

Among 19 patients who had 6-month follow-up transthoracic echocardiograms, Doppler evidence of atrial septal shunting was present in four, absent in seven, and indeterminate in eight3. 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: 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.

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Table 1 Inclusion criteria for identification of relevant studies Characteristic Criteria Publication type 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. Patient Patients with mitral regurgitation. Intervention/test Percutaneous mitral valve leaflet repair. Outcome Articles were retrieved if the abstract contained information relevant to the safety and/or efficacy. Language 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.

Interventional procedures

• Thoracoscopically assisted mitral valve surgery. NICE interventional procedures guidance 245 (2007). Available from www.nice.org.uk/IPG245

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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 Procedural success Complications These patients were part of • 72% (34/47) of patients had a successful procedure 2 patients had surgery before EVEREST – a multicentre (defined as placement of a clip with discharge: 1 for delivery phase I safety and feasibility Study type: multicentre case series (phase I trial of the Mitraclip device. trial) echocardiographic core laboratory reduction in MR catheter malfunction and the at discharge to at least grade 2+). other because of partial clip Country: USA • In 5 patients, the clip was not left in place due to detachment. The stated study objective Study period: not stated insufficient MR reduction (3 patients were enrolled was to assess the impact of a Study population: patients with moderate to before placement of a second clip was allowed in standardised severe (grade 3) or severe (grade 4) MR the protocol). None of these 5 patients had major echocardiographic protocol Aetiology: degenerative disease of the MV adverse events and all had elective surgery: 4 had for the guidance of the (87%), functional or ischaemic MR (13%) repair procedures and 1 had mitral valve procedure (for example, on reducing procedure time). n = 47 replacement as intended.

Mean age: 67 years (±12 years) Mitral regurgitation grading: Sex: not stated grade 1: mild Inclusion criteria: grade 2: moderate • Met American Heart Association criteria for grade 3: moderate to severe MV repair. grade 4: severe. • Transthoracic and transoesophageal echocardiograms showing at least three of the six American Society of Echocardiography criteria for moderate to severe or severe MR.

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

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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 (2005)3 Technical success of procedure In-hospital complications These patients • Successful clip implantation: 24/27 (89%): • 1 patient required a blood were part of product transfusion. EVEREST – a Study type: multicentre case - 22 patients were discharged from hospital with clips in place multicentre phase I series (phase I trial) - 2 patients were discharged from hospital without a clip. In 1 patient, control • There were no cases of safety and Country: USA of MR was not adequate after implantation but the clip could not be mechanical ventilation feasibility trial of the > 24 hours, new onset atrial Study period: not stated re-opened (device malfunction) so the clip was left in place. In the other Mitraclip device. patient there was partial clip detachment detected at 24-hour follow-up (see fibrillation, access site Study population: patients with safety section). Both patients had subsequent elective surgical MV repair. complications requiring surgery, moderate-to-severe (grade 3) or or renal failure or dialysis. These patients are severe (grade 4) MR • Unsuccessful clip implantation: 3/27 (11%): likely to be the Aetiology: degenerative disease of - in all 3 patients, the clip and delivery system were uneventfully removed same as those in 30-day major adverse events: the MV (93%), functional or during the procedure without major adverse events. Two patients had the study by 4/27 (15%) ischaemic MR (7%) subsequent elective surgical MV repair and 1 patient had elective intended Silvestry et al. MV replacement. (2007). n = 27 • 1 patient had a permanent stroke (non-embolic stroke Mean age: 69 years (±13 years) associated with post-procedure MR severity Sex: 59% male hypotension). Of the 22 patients who were discharged with a clip in place, MR severity was Comorbidities: history of congestive • 3 patients had clip detachment measured by core laboratory assessments. heart failure (59%), NYHA class III from one of the two valve or IV (44%), atrial fibrillation (41%) Discharge 30 days 6 months leaflets. One was detected at Grade ≤ 2+ 18/22 (82%) 14/22 (64%) 14/22 (64%) Inclusion criteria: 1 the 24-hour follow-up Grade ≥ 3+ 4/22 (18%) 6/22 (27%) 4/22 (18%) echocardiogram and the other • Symptomatic or if Not assessed 0 2 42 1 two were detected at the 30-day asymptomatic: These patients had MR grade 4+ at baseline and although they improved to grade 3+ follow-up echocardiogram. • Left ventricular ejection at discharge, they did not improve to grade 2+ or less in the short term. 2 These patients required subsequent elective valve surgery. • There were no cases of fraction < 60% or myocardial infarction, cardiac • Left ventricular end-systolic 30-day follow-up tamponade or septicaemia. dimension > 45 mm • 2 patients had recurrence of MR at 30 days. • 2 patients had partial clip detachment. 6-month follow-up Technique: percutaneous MV Among 19 patients with 6 month leaflet repair using the Mitraclip 6-month follow-up follow-up transthoracic device (Evalve Inc., California) • Of the patients having 6-month transthoracic echocardiograms (n = 19), echocardiograms, Doppler evidence of atrial septal shunting was present in 4, absent in 7 and evidence of atrial septal shunting Follow-up: 6 months indeterminate in 8. was present in four, absent in seven and indeterminate in eight. Conflict of interest: none stated • 4 patients required elective valve surgery within 6 months.

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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 In 3 patients, no clip was placed (no further information stated); 6 patients had their clips No safety outcomes These patients explanted by 6 months (range 1–133 days, none for mitral stenosis; no further information were reported in this were part of stated); 4 patients received two clips (‘in 1 patient the first clip was not optimally placed and publication (see study EVEREST – a Study type: multicentre case surgery was performed within 30 days’). by Feldman et al. multicentre phase I series (phase I trial) 2005) safety and Country: USA feasibility trial of Mitral valve area and gradient – before discharge from hospital Study period: not stated the Mitraclip Haemodynamic outcomes were assessed immediately after the procedure and device. Study population: patients with echocardiographic outcomes were assessed on the day of hospital discharge (mean moderate to severe (grade 3) or 1.8 days postoperatively). severe (grade 4) MR These patients are Preoperative Postoperative p-value Aetiology: degenerative disease of the same as those the MV (93%), functional or Mean MV gradient by Doppler (mmHg) 1.79 ± 0.89 3.31 ± 2.09 0.004 included in the ischaemic MR (7%) (n = 16) study by Feldman et al. (2005). n = 27 Mean MV gradient by haemodynamics 5.00 ± 3.38 3.5 ± 3.34 0.2 (mmHg) (n = 8) Mean age: 69 years (±13 years) Peak MV gradient by Doppler (mmHg) 6.26 ± 2.79 7.09 ± 2.88 0.248 Sex: 59% male (n = 18) Comorbidities: history of congestive MV area by planimetry (cm2) (n = 18) 6.49 ± 1.61 4.46 ± 2.14 0.000036 heart failure (59%), NYHA class III 2 or IV (44%), atrial fibrillation (41%) MV area by pressure half-time (cm ) 4.35 ± 0.98 3.01 ± 1.42 0.03781 (n = 7) Inclusion criteria: MV area by Gorlin formula (cm2) (n = 8) 2.78 ± 1.01 3.05 ± 0.90 0.6 • Symptomatic or if asymptomatic: • Left ventricular ejection Mitral valve area and gradient – at 12-month follow-up fraction < 60% or Discharge 12 months p-value • Left ventricular end-systolic Mean MV gradient by Doppler (mmHg) (n = 13) 3.22 ± 2.17 3.56 ± 098 0.508 dimension > 45 mm Peak MV gradient by Doppler (mmHg) (n = 12) 5.92 ± 2.53 9.90 ± 4.28 0.0076 MV area by planimetry (cm2) (n = 13) 3.90 ± 1.90 3.79 ± 1.54 0.785 Technique: percutaneous MV MV area by pressure half-time (cm2) (n = 5) 4.60 ± 0.63 2.90 ± 0.91 0.02 leaflet repair using the Mitraclip device (Evalve Inc., California) Other

There was a significant reduction in MR in 14 patients, which lasted up to at least 1 year in Follow-up: 12 months 13 patients. Conflict of interest: none stated

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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 Complications These patients were part of The 6 patients required subsequent surgical intervention (55.5 ± 55 days EVEREST – a multicentre later, range 1–133 days) for recurrent or persistent MR. phase I safety and Study type: case series feasibility trial of the Country: USA • Four patients had malpositioning of the clip at the time of implantation (in Mitraclip device. 3 patients the clip partially detached from either the anterior or posterior Study period: not stated leaflets). Study population: patients from three • Two patients had insufficient MR reduction at the time of implantation (in These patients are the centres with MR after percutaneous clip 1 patient the clip was placed suboptimally and could not be repositioned same as those included in deployment for MV repair and who later due to a malfunction of the delivery catheter). the studies by Feldman et required surgical intervention. The al. (2005) and Herrmann et patients were part of a group of 27 al. (2006). patients enrolled in a phase I clinical Outcome of surgical revision trial of the Mitraclip device. In all patients, the clip was removed from the leaflets without difficulty. Five n = 6 patients required MV repair and 1 patient underwent MV replacement.

• Five patients recovered well without any complications and reported an Technique: percutaneous edge-to-edge improvement in symptoms. repair using the Mitraclip device (Evalve • One patient developed a right-sided ilio-femoral deep venous thrombosis Inc., California) on the same side as the catheter insertion site 3 days after the surgical intervention and 4 days after the percutaneous procedure. The patient Mean follow-up: 55 days was maintained on anticoagulation therapy. The patient also developed a symptomatic pericardial effusion that required percutaneous

pericardiocentesis. Conflict of interest: six authors disclosed a financial relationship with the manufacturer 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).

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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 Echocardiography immediately after the procedure and 24 hours later Complications showed the clip was well placed. There were no Study type: case series Exertional dyspnoea resolved within 30 days of the procedure and the complications patient remained asymptomatic with mild MR 2 years after the procedure reported. Country: Venezuela (MR reduced from grade 4 preoperatively to grade 1 at 1- and 2-year Study period: June 2003 follow-up). 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

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

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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 trans- septal 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’.

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References 1. Condado JA, Acquatella H, Rodriguez L et al. (2006) Percutaneous edge- to-edge mitral valve repair: 2-year follow-up in the first human case. Catheterization and Cardiovascular Interventions 67: 323-325.

2. 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: 1131-1140.

3. Feldman T, Wasserman HS, Herrmann HC et al. (2005) Percutaneous mitral valve repair using the edge-to-edge technique: six-month results of the EVEREST Phase I Clinical Trial. Journal of the American College of Cardiology 46: 2134-2140.

4. 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: 821-828.

5. 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: 2338-2342

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Appendix A: Additional papers on percutaneous mitral valve leaflet repair

There were no additional papers identified.

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Appendix B: Related NICE guidance for percutaneous mitral valve leaflet repair

Guidance Recommendations Interventional Thoracoscopically assisted mitral valve surgery. NICE procedures interventional procedures guidance 245 (2007).

1.1. 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. 1.2. 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.

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Appendix C: Literature search for percutaneous mitral valve leaflet repair

Database Date searched Version No. searched retrieved Cochrane Database of Systematic 08/08/2008 Issue 3, 2008 0 Reviews – CDSR (Cochrane Library) Database of Abstracts of Reviews of 08/08/2008 – 0 Effects – DARE (CRD website) HTA database (CRD website) 08/08/2008 – 0 Cochrane Central Database of 08/08/2008 Issue 3, 2008 9 Controlled Trials – CENTRAL (Cochrane Library) MEDLINE (Ovid) 07/08/2008 1950 to July 179 Week 5 2008 MEDLINE In-Process (Ovid) 07/08/2008 15 EMBASE (Ovid) 07/08/2008 1980 to Week 183 32 2008 CINAHL (NLH Search 2.0) 08/08/2008 1981 to present 22 BLIC (Dialog DataStar) 11/08/2008 – 0 National Research Register (NRR) 11/08/2008 – 0 Archive UK Clinical Research Network 11/08/2008 – 0 (UKCRN) Portfolio Database Current Controlled Trials 11/08/2008 – 2 metaRegister of Controlled Trials - mRCT Clinicaltrials.gov 11/08/2008 – 2

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. IP overview: percutaneous mitral valve leaflet repair Page 15 of 16 IP 664

9 (bicuspid adj3 valve$).tw. 10 (cardiac adj3 valve$).tw. 11 or/5-10 12 (repair$ or reconstruc$ or clos$).tw. 13 11 and 12 14 Mitral Valve Insufficiency/ 15 (Mitral adj3 insufficien$).tw. 16 (Mitral adj3 regurgitat$).tw. 17 (mitral adj3 incompet$).tw. 18 or/14-17 19 4 and 13 and 18 20 Mitraclip.tw. 21 19 or 20

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