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ª 2 0 1 6 B Y T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y F O UN DA T I O N I S S N 1 9 3 6 - 8 7 9 8 / $ 3 6 . 0 0

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STRUCTURAL

Transcatheter Mitral Valve Replacementin Native Mitral Valve Disease WithSevere Mitral Annular Calcification

Results From the First Multicenter Global Registry

Mayra Guerrero, MD,a Danny Dvir, MD,b Dominique Himbert, MD,c Marina Urena, MD,c Mackram Eleid, MD,d

Dee Dee Wang, MD,e Adam Greenbaum, MD,e Vaikom S. Mahadevan, MBBS, MD,f David Holzhey, MD, PHD,g

Daniel O’Hair, MD,h Nicolas Dumonteil, MD,i Josep Rodés-Cabau, MD,j Nicolo Piazza, MD,k Jose H. Palma, MD, PHD,l

Augustin DeLago, MD,m Enrico Ferrari, MD,n AdamWitkowski, MD, PHD,o Olaf Wendler, MD, PHD,p

Ran Kornowski, MD,q Pedro Martinez-Clark, MD,r Daniel Ciaburri, MD,s Richard Shemin, MD,t Sami Alnasser, MD,u

David McAllister, DO,v Martin Bena, MD,w Faraz Kerendi, MD,x Gregory Pavlides, MD,y Jose J. Sobrinho, MD,z

Guilherme F. Attizzani, MD,aa Isaac George, MD,bb George Nickenig, MD,cc Amir-Ali Fassa, MD,dd Alain Cribier, MD,ee

VinnieBapat,MD,ff Ted Feldman,MD,a Charanjit Rihal,MD,d Alec Vahanian,MD,c JohnWebb,MD,bWilliamO’Neill,MDe

JACC: CARDIOVASCULAR INTERVENTIONS CME

This article has been selected as this issue’s CME activity, available online

at http://www.acc.org/jacc-journals-cme by selecting the CME tab on the

top navigation bar.

Accreditation and Designation Statement

The American College of Cardiology Foundation (ACCF) is accredited by

the Accreditation Council for Continuing Medical Education (ACCME) to

provide continuing medical education for physicians.

The ACCF designates this Journal-based CME activity for a maximum

of 1 AMA PRA Category 1 Credit(s)�. Physicians should only claim credit

commensurate with the extent of their participation in the activity.

Method of Participation and Receipt of CME Certificate

To obtain credit for this CME activity, you must:

1. Be an ACC member or JACC: Cardiovascular Interventions subscriber.

2. Carefully read the CME-designated article available online and in this

issue of the journal.

3. Answer the post-test questions. At least 2 out of the 3 questions

provided must be answered correctly to obtain CME credit.

4. Complete a brief evaluation.

5. Claim your CME credit and receive your certificate electronically by

following the instructions given at the conclusion of the activity.

CME Objective for This Article: 1) appreciate the risks of mitral valve

replacement in the setting of severemitral annular calcification; 2) evaluate

the clinical outcomes following transcatheter mitral valve replacement

with balloon-expandable valves in high-risk patients; and 3) consider the

significance of computed tomography for pre-procedural planning when

transcatheter mitral valve replacement is the treatment of choice.

CME Editor Disclosure: JACC: Cardiovascular Interventions CME Editor Bill

Gogas, MD, PhD, has reported that he has no disclosures.

Author Disclosures: Dr. Guerrero has served as a proctor and consultant for

and received research grant support from Edwards Lifesciences. Dr. Dvir has

served as a consultant to Edwards Lifesciences. Dr. Himbert has served as a

proctor for Edwards Lifesciences andMedtronic; and a consultant for

Edwards Lifesciences. Dr. Greenbaum has served as a proctor for Edwards

Lifesciences.Dr.Mahadevanhas servedasaproctor forEdwardsLifesciences.

Dr.Holzheyhas served as a proctor for Symetis; andon theadvisoryboard for

Edwards Lifesciences andMedtronic. Dr. O’Hair is a consultant toMedtronic.

Dr. Dumonteil has served as a proctor for Edwards Lifesciences, Medtronic,

and Boston Scientific; and consultant to Biotronik. Dr. Rodes-Cabau has

served as a consultant to St. Jude Medical. Dr. Piazza has served as a

consultant to Medtronic and HighLife; and received research grant support

fromMedtronic.Dr.FerrarihasservedasaproctorandconsultantforEdwards

Lifesciences. Dr. Witkowski has received speakers fees from Edwards

Lifesciences.Dr.Wendler has served as a consultant toEdwardsLifesciences,

St. Jude Medical, and JenaValve; on the Speakers Bureau for Edwards

Lifesciences; and as a proctor for the Edwards Lifesciences THV Program. Dr.

Shemin has served as a consultant for Edwards Lifesciences and Sorin. Dr.

McAllister has served as a proctor forMedtronic. Dr. Attizzani has served as a

proctor for Edwards Lifesciences andMedtronic; on the Speakers Bureau for

Medtronic and Abbott Vascular; and as a consultant to St. Jude Medical. Dr.

George is a consultant to Edwards Lifesciences andMedtronic. Dr. Cribier has

served as a consultant to Edwards Lifesciences. Dr. Bapat has served as a

consultant to Edwards Lifesciences, Medtronic, Sorin, Boston Scientific, and

Sorin; and as a proctor for Edwards Lifesciences. Dr. Feldman has served as a

consultant and received research grant support from Abbott, Boston

Scientific, andEdwards Lifesciences. Dr. Vahanian has served as a consultant

to Edwards Lifesciences, Medtronic, and Abbott Vascular; and has received

research grant support from Valtech. Dr. Webb has served as a consultant to

Edwards Lifesciences. Dr. O’Neill has served as a proctor and consultant for

Edwards Lifesciences; has served as a consultant for St. Jude Medical and

Medtronic; and is the director of Neovasc Inc. All other authors report that

they have no relationships relevant to the contents of this paper to disclose.

Medium of Participation: Print (article only); online (article and quiz).

CME Term of Approval

Issue Date: July 11, 2016

Expiration Date: July 10, 2017

Guerrero et al. J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 9 , N O . 1 3 , 2 0 1 6

TMVR for Severe Mitral Annular Calcification J U L Y 1 1 , 2 0 1 6 : 1 3 6 1 – 7 1

1362

Transcatheter Mitral Valve Replacementin Native Mitral Valve Disease WithSevere Mitral Annular Calcification

Results From the First Multicenter Global Registry

Mayra Guerrero, MD,a Danny Dvir, MD,b Dominique Himbert, MD,c Marina Urena, MD,c Mackram Eleid, MD,d

Dee Dee Wang, MD,e Adam Greenbaum, MD,e Vaikom S. Mahadevan, MBBS, MD,f David Holzhey, MD, PHD,g

Daniel O’Hair, MD,h Nicolas Dumonteil, MD,i Josep Rodés-Cabau, MD,j Nicolo Piazza, MD,k Jose H. Palma, MD, PHD,l

Augustin DeLago, MD,m Enrico Ferrari, MD,n Adam Witkowski, MD, PHD,o Olaf Wendler, MD, PHD,p

Ran Kornowski, MD,q Pedro Martinez-Clark, MD,r Daniel Ciaburri, MD,s Richard Shemin, MD,t Sami Alnasser, MD,u

David McAllister, DO,v Martin Bena, MD,w Faraz Kerendi, MD,x Gregory Pavlides, MD,y Jose J. Sobrinho, MD,z

Guilherme F. Attizzani, MD,aa Isaac George, MD,bb George Nickenig, MD,cc Amir-Ali Fassa, MD,dd Alain Cribier, MD,ee

Vinnie Bapat, MD,ff Ted Feldman, MD,a Charanjit Rihal, MD,d Alec Vahanian, MD,c John Webb, MD,b

William O’Neill, MDe

ABSTRACT

Fro

St.dD

He

Sa

Au

Fra

dio

MenC

An

OBJECTIVES This study sought to evaluate the outcomes of the early experience of transcatheter mitral valve

replacement (TMVR) with balloon-expandable valves in patients with severe mitral annular calcification (MAC) and

reports the first large series from a multicenter global registry.

BACKGROUND The risk of surgical mitral valve replacement in patients with severe MAC is high. There are isolated

reports of successful TMVR with balloon-expandable valves in this patient population.

METHODS We performed a multicenter retrospective review of clinical outcomes of patients with severe MAC under-

going TMVR.

RESULTS From September 2012 to July of 2015, 64 patients in 32 centers underwent TMVR with compassionate use of

balloon-expandable valves. Mean age was 73 � 13 years, 66% were female, and mean Society of Thoracic Surgeons score

was 14.4 � 9.5%. The mean mitral gradient was 11.45 � 4.4 mm Hg and the mean mitral area was 1.18 � 0.5 cm2. SAPIEN

valves (Edwards Lifesciences, Irvine, California) were used in 7.8%, SAPIEN XT in 59.4%, SAPIEN 3 in 28.1%, and Inovare

(Braile Biomedica, Brazil) in 4.7%. Access was transatrial in 15.6%, transapical in 43.8%, and transseptal in 40.6%.

Technical success according to Mitral Valve Academic Research Consortium criteria was achieved in 46 (72%) patients,

primarily limited by the need for a second valve in 11 (17.2%). Six (9.3%) had left ventricular tract obstruction with

hemodynamic compromise. Mean mitral gradient post-procedure was 4 � 2.2 mm Hg, paravalvular regurgitation was

mild or absent in all. Thirty-day all-cause mortality was 29.7% (cardiovascular ¼ 12.5% and noncardiac ¼ 17.2%); 84% of

the survivors with follow-up data available were in New York Heart Association functional class I or II at 30 days (n ¼ 25).

CONCLUSIONS TMVR with balloon-expandable valves in patients with severe MAC is feasible but may be associated

with significant adverse events. This strategy might be an alternative for selected high-risk patients with limited treat-

ment options. (J Am Coll Cardiol Intv 2016;9:1361–71) © 2016 by the American College of Cardiology Foundation.

m aDepartment of Medicine, Division of Cardiology, Evanston Hospital, Evanston, Illinois; bCenter for Heart Valve Innovation,

Paul’s Hospital, Vancouver, British Columbia, Canada; cCardiology Department, Bichat-Claude Bernard Hospital, Paris, France;

epartment of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota; eDepartment of Medicine, Division of Cardiology,

nry Ford Hospital, Detroit, Michigan; fDepartment of Medicine, Division of Cardiology, University of California San Francisco,

n Francisco, California; gDepartment of Cardiac Surgery, Leipzig Heart Center, Leipzig, Germany; hDepartment of Surgery,

rora St. Luke’s Medical Center, Milwaukee, Wisconsin; iDepartment of Cardiology, Rangueil University Hospital, Toulouse,

nce; jQuebec Heart and Lung Institute, Laval University, Quebec City, Quebec, Canada; kDepartment of Interventional Car-

logy, McGill University Health Centre, Montreal, Quebec, Canada; lDepartment of Cardiovascular Surgery, Escola Paulista de

dicina, São Paolo, Brazil; mDepartment of Medicine, Division of Cardiology, Albany Medical Center Hospital, Albany, New York;

ardiac Surgery Unit, Cardiocentro Ticino Foundation, Lugano, Switzerland; oDepartment of Interventional Cardiology &

giology, Institute of Cardiology, Warsaw, Poland; pDepartment of Surgery, King’s College Hospital, London, United Kingdom;

J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 9 , N O . 1 3 , 2 0 1 6 Guerrero et al.J U L Y 1 1 , 2 0 1 6 : 1 3 6 1 – 7 1 TMVR for Severe Mitral Annular Calcification

1363

AB BR E V I A T I O N S

AND ACRONYM S

CT = computed tomography

LVOT = left ventricular

outflow tract

MAC = mitral annular

calcification

MR = mitral regurgitation

MV = mitral valve

MVA = mitral valve area

MVARC = Mitral Valve

Academic Research Consortium

P atients with mitral annular calcification (MAC)are an elderly high-risk patient populationwith multiple comorbidities even before they

develop valvular dysfunction. They have higher riskof cardiovascular disease, cardiovascular death, andall-cause mortality (1–3). The risk of surgical mitralvalve (MV) replacement in this population is highdue to comorbidities and technical challenges relatedto calcium burden (4) precluding successful surgeryin many. Rupture of the posterior wall of the leftventricle has been reported as a potential complica-tion (5). There is currently an unmet clinical need

SEE PAGE 1372 MVG = mitral valve gradient

NYHA = New York Heart

Association

THV = transcatheter heart

valve

TMVR = transcatheter mitral

replacement

for many who are not treated due to their high surgi-cal risk. There have been isolated reports ofsuccessful transcatheter MV replacement (TMVR)with the compassionate use of balloon-expandabletranscatheter aortic valves in this patient population(Edwards Lifesciences, Irvine, California). The firstfew procedures were performed utilizing a surgicaltransapical (6,7) or an open transatrial approach (8),but subsequent reports described successful implan-tation with a completely percutaneous transfemoralapproach (9–11). Although these case reports areencouraging, the safety and efficacy of this procedureare unknown. We hypothesized that TMVR with

qDepartment of Medicine, Division of Cardiology, Rabin Medical Center, Peta

Cardiology, Angiografía de Occidente, Cali, Colombia; sDepartment of SurtDepartment of Surgery, UCLA Medical Center, Los Angeles, California; uD

Michael’s Hospital, Toronto, Canada; vDepartment of Medicine, Division of CwDepartment of Cardiac Surgery, National Institute of Cardiovascular Dise

Heart Hospital of Austin, Austin, Texas; yDepartment of Medicine, Division o

Nebraska; zDepartment of Surgery, Complexo Hospitalar de Niteroi, Nitero

tional Center, University Hospitals Case Medical Center, Cleveland, Ohio; bbC

Hospital-Columbia University Medical Center, New York, New York; ccHear

partment of Medicine, Division of Cardiology, Hôpital de La Tour, Geneva, Sw

Rouen’s Charles Nicolle Hospital, Rouen, France; and the ffDepartment of Ca

London, United Kingdom. Dr. Guerrero has served as a proctor and consultant

Lifesciences.Dr.Dvirhas served as a consultant toEdwards Lifesciences.Dr.Hi

and Medtronic; and a consultant for Edwards Lifesciences. Dr. Greenbaum h

Mahadevan has served as a proctor for Edwards Lifesciences. Dr. Holzhey has

board for Edwards Lifesciences and Medtronic. Dr. O’Hair is a consultant to

EdwardsLifesciences,Medtronic,andBostonScientific; andconsultant toBiotr

JudeMedical. Dr. Piazza has served as a consultant toMedtronic andHighLife;

Dr. Ferrari has served as a proctor and consultant for Edwards Lifesciences. Dr

Lifesciences. Dr. Wendler has served as a consultant to Edwards Lifescience

Bureau for Edwards Lifesciences; and as a proctor for the Edwards Lifescience

for Edwards Lifesciences and Sorin. Dr. McAllister has served as a proctor fo

Edwards Lifesciences and Medtronic; on the Speakers Bureau for Medtronic

Medical. Dr. George is a consultant to Edwards Lifesciences and Medtronic. D

sciences. Dr. Bapat has served as a consultant to Edwards Lifesciences,Medtron

for Edwards Lifesciences. Dr. Feldmanhas served as a consultant and received

andEdwards Lifesciences. Dr. Vahanianhas servedas a consultant to Edwards

received researchgrant support fromValtech.Dr.Webbhas servedas a consult

proctor and consultant for Edwards Lifesciences; has served as a consultant for

Neovasc Inc. All other authors report that they have no relationships relevant

Manuscript received March 14, 2016; accepted April 18, 2016.

balloon-expandable valves is a feasible alter-native therapeutic option in selected patientswith severe MAC who cannot have surgery.We established the TMVR in MAC Global Reg-istry to collect outcomes data of similar pro-cedures performed worldwide to betterunderstand its safety and efficacy in a largerpatient population.

METHODS

The TMVR in MAC Global Registry was initi-ated in October of 2013. Centers around theworld with experience of TMVR using balloon-expandable valves in patients with MAC wereinvited to participate (Online Appendix).Sixty-four patients from 32 centers in NorthAmerica, Europe, and South America who un-derwent TMVR with compassionate use of

balloon-expandable transcatheter heart valve (THV)between September of 2012 and July of 2015 wereincluded. The study was approved by the InstitutionalReview Board of the NorthShore University Health-System Research Institute. The inclusion criteria werethe presence of symptomatic severe mitral valvulardisease with severe MAC in patients not eligible forstandard MV surgery due to comorbidities or technical

valve

h Tikva, Israel; rDepartment of Medicine, Division of

gery, Saint Francis Medical Center, Peoria, Illinois;

epartment of Medicine, Division of Cardiology, St.

ardiology, The Iowa Heart Center, Des Moines, Iowa;

ases, Bratislava, Slovakia; xDepartment of Surgery,

f Cardiology, The Nebraska Medical Center, Omaha,

i, Brasil; aaThe Valve and Structural Heart Interven-

olumbia Heart Valve Center, New York Presbyterian

t Center, University of Bonn, Bonn, Germany; ddDe-

itzerland; eeDepartment of Cardiology, University of

rdiology and Cardiac Surgery, St. Thomas’ Hospital,

for and received research grant support fromEdwards

mberthas servedas a proctor forEdwards Lifesciences

as served as a proctor for Edwards Lifesciences. Dr.

served as a proctor for Symetis; and on the advisory

Medtronic. Dr. Dumonteil has served as a proctor for

onik.Dr.Rodes-Cabauhas servedasa consultant toSt.

and received research grant support fromMedtronic.

. Witkowski has received speakers fees from Edwards

s, St. Jude Medical, and JenaValve; on the Speakers

s THV Program. Dr. Shemin has served as a consultant

r Medtronic. Dr. Attizzani has served as a proctor for

and Abbott Vascular; and as a consultant to St. Jude

r. Cribier has served as a consultant to Edwards Life-

ic, Sorin, Boston Scientific, andSorin; andas a proctor

research grant support fromAbbott, Boston Scientific,

Lifesciences,Medtronic, andAbbott Vascular; andhas

ant toEdwards Lifesciences.Dr.O’Neill has servedas a

St. JudeMedical andMedtronic; and is the director of

to the contents of this paper to disclose.

FIGURE 1 Cardiac Computed Tomography

(A) Cardiac computed tomography–based measurement of the calcified mitral annulus using 3Mensio Structural Heart Mitral Workflow version 7.0

(PieMedical Imaging,Maastricht, theNetherlands). (B)Mitral annularmeasurementsmanually tracedusingOsiriX imaging software (Pixmeo,Bernex,

Switzerland). (C) Aortomitral angle measurement and virtual valve simulation and (D) transapical access planning using 3Mensio version 8.0.

Guerrero et al. J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 9 , N O . 1 3 , 2 0 1 6

TMVR for Severe Mitral Annular Calcification J U L Y 1 1 , 2 0 1 6 : 1 3 6 1 – 7 1

1364

reasons related to calcium burden. A quantitativedefinition of severe MAC was not specified. However,most operators considered severe MAC the presence ofdiffuse almost circumferential heavy calcification ofthe MV ring as seen by cardiac computed tomography(CT) (Figure 1). Data were collected retrospectively forthe procedures performed before the registry wasinitiated and prospectively thereafter in the majorityof the patients, using a standardized case report formand included: 1) Baseline clinical characteristics,baseline echocardiographic characteristics, and CT-based MV annulus diameter and area measurementswhen available; 2) procedural characteristics includingtype and size of THV implanted, valve deliveryapproach, and technical success; early post-implantation echocardiographic evaluation includingejection fraction, mean MV gradient (MVG), MV area(MVA), and left ventricular outflow tract (LVOT)gradient; and 3) procedural complications and majoradverse eventswere collected at discharge, 30days, and1 year, and New York Heart Association (NYHA) func-tional class at 30 days and 1 year. The follow-up datawere reported according to the lapse of time between

the index procedure and data lock for this analysis(September 2, 2015).

DEFINITIONS. Technical success (measured at exitfrom the cardiac catheterization/operating room) wasdefined according to the Mitral Valve AcademicResearch Consortium (MVARC) criteria (12) as a pro-cedure meeting all of the following: absence of pro-cedural mortality; successful access, delivery, andretrieval of the device delivery system; and success-ful deployment and correct positioning of the firstintended device; and freedom from emergent surgeryor reintervention related to the device or access.Periprocedural death was defined as death occurringwithin 30 days on the intervention or beyond 30 daysfor patients not yet discharged. All clinical endpointswere also defined according to MVARC criteria.

STATISTICAL ANALYSIS. Continuous variables weresummarized as mean � SD or median (range). Cate-gorical variables were summarized as frequency andpercentage. Repeated measures analysis of variancewas used to compare clinical parameters amongdifferent time points. Mean difference, standard

TABLE 1 Baseline Patient Characteristics

Age, yrs 73 � 13

Female 40/61 (66)

Diabetes 24/61 (39)

Atrial fibrillation 24/54 (44.4)

Peripheral arterial disease 19/60 (31.7)

Chronic obstructive pulmonary disease 28/61 (45.9)

Chronic renal failure 32/62 (51.6)

Prior TIA or stroke 10/60 (16.7)

Hospitalization due to heart failureduring prior 12 months

43/60 (71.7)

Prior CABG 20/61 (32.8)

Prior AVR 34/62 (54.8)

TAVR 9/34 (26.5)

SAVR 25/34 (73.5)

Mechanical 10/25 (40)

Bioprosthetic 15/25 (60)

Receiving long-term anticoagulation 26/50 (52)

Prior MV balloon commissurotomy/valvuloplasty 6/58 (10.3)

STS score 14.4 � 9.5

NYHA functional class

II 5/62 (8.1)

III 24/62 (38.7)

IV 33/62 (53.2)

EF 59.5 � 11.3

Mean MVG 11.4 � 4.4

MVA 1.18 � 0.51

Systolic PAP, mm Hg 56.2 � 19

LVOT gradient 6.4 � 18.2

3(þ) MR 11/61 (18)

4(þ) MR 10/61 (16.4)

Values are mean � SD or n/N (%).

AVR ¼ aortic valve replacement; CABG ¼ coronary artery bypass graft; EF ¼ejection fraction; LVOT ¼ left ventricular outflow tract; MR ¼ mitral regurgitation;MV ¼ mitral valve; MVA ¼mitral valve area; MVG ¼mitral valve gradient; NYHA ¼New York Heart Association; PAP ¼ pulmonary artery pressure; SAVR ¼ surgicalaortic valve replacement; STS ¼ Society of Thoracic Surgeons; TAVR ¼ trans-catheter aortic valve replacement; TIA ¼ transient ischemic attack.

TABLE 2 Procedural Results

Procedural characteristics

Device brand

Edwards

SAPIEN 5/64 (7.8)

SAPIEN XT 38/64 (59.4)

SAPIEN 3 18/64 (28.1)

Inovare 3/64 (4.7)

Device size, mm

23 2/64 (3.1)

26 28/64 (43.8)

29 31/64 (48.4)

25 (Inovare) 1/64 (1.6)

30 (Inovare) 2/64 (3.1)

Access

Transapical 29/64 (45.3)

Direct open transatrial 9/64 (14.1)

Transseptal 26/64 (40.6)

Traditional (wire free in LV) 22/26

Modified (wire externalizedthrough percutaneoussheath in LV)

4/26

Pre-dilation 21/58 (36.1)

AVR during same procedure 12/64 (18.7)

TAVR 7/12 (58.3)

SAVR 5/12 (41.7)

Procedural results

Technical success* 46/64 (72)

Post-implantation valvuloplasty 18/58 (31)

Mean MVG 4 � 2.2

MVA 2.2 � 0.95

LVOTO with hemodynamic compromise 6/64 (9.3)

Valve embolization 4/64 (6.25)

Need for a second valve 11/64 (17.2)

Due to MR 6/11 (55)

Due to migration 5/11 (45)

LV perforation 2/64 (3.1)

Pulmonary vein perforation 1/64 (1.56)

Conversion to open heart surgery 4/64 (6.25)

LVOTO 1/4 (25)

Embolization 2/4 (50)

LV perforation 1/4 (25)

Residual MR at end of procedure

Trace or none 35/52 (67.3)

Mild 17/52 (32.7)

$3(þ) 0/52 (0)

Values are n/N (%) or mean � SD. *According to Mitral Valve Academic ResearchConsortium definition.

LV ¼ left ventricle; other abbreviations as in Table 1.

J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 9 , N O . 1 3 , 2 0 1 6 Guerrero et al.J U L Y 1 1 , 2 0 1 6 : 1 3 6 1 – 7 1 TMVR for Severe Mitral Annular Calcification

1365

error, and adjusted p values were reported. Percent-ages were on the basis of all known values if themissing items were <5%. Missing data items resultedin reduced denominators for many variables. If 5% ormore of the values are missing for a particular vari-able, the number of known values was indicated andincluded in the denominator. Statistical analysis wasperformed using SAS 9.3 platform (SAS Institute,Cary, North Carolina). A p value <0.05 was consid-ered statistically significant.

RESULTS

PATIENT CHARACTERISTICS. Baseline patient char-acteristics are listed in Table 1. Mean age was 73 � 13years (range 39 to 96 years), and 66% were female.Multiple comorbidities were present. Thirty-four of62 (54.8%) patients had a prior aortic valve replace-ment of which 9 (26.5%) were THV, 8 were Edwards, 1

was CoreValve (Medtronic, Minneapolis, Minnesota),and 25 (73.5%) were surgical aortic valves (10 me-chanical and 15 bioprosthetic). The mean Society ofThoracic Surgeons score was 14.4 � 9.5 (range 1 to41.5). The reason for inoperability was deemed to betechnical in 18.5%, due to comorbidities in 25.5% andboth in 55%. Left ventricular ejection fraction waspreserved in most patients (59.5 � 11.3%). The

Guerrero et al. J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 9 , N O . 1 3 , 2 0 1 6

TMVR for Severe Mitral Annular Calcification J U L Y 1 1 , 2 0 1 6 : 1 3 6 1 – 7 1

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primary MV pathology was stenosis in 93.5% and6.5% had primarily mitral regurgitation (MR). Themean MVG in patients with stenosis was 11.4 � 4.4mm Hg and the mean MVA was 1.18 � 0.51 cm2. Themean pre-existing LVOT gradient was 6.4 � 18.2mm Hg (range 0 to 60 mm Hg). Most patients were inNYHA functional class III or IV (91.9%).

PROCEDURAL RESULTS. The procedural results aresummarized in Table 2. The transatrial delivery underdirect visualization through an open surgicalapproach was utilized in a minority of cases (10 of 64[15.6%]). Two to 3 sutures were used to help securethe stent frame to the annulus, and in some cases theanterior mitral leaflet was resected to reduce risk ofLVOT obstruction. In 1 case, the annulus was too large(area 703 mm2), for which a 32 mm Physio ring(Edwards Lifesciences) was sutured to provide a

FIGURE 2 Delivery Approaches Utilized in This Registry

(A) Open transatrial; (B) transapical; (C) transseptal; (D) modified trans

percutaneously placed in the left ventricle.

landing zone prior to deployment of a 29 mm SAPIENXT (Edwards Lifesciences) valve. Transapical andtransseptal approaches were used in most cases, 28 of64 (43.8%) and 26 of 64 (40.6%), respectively. In 4 ofthe 26 transseptal procedures (15.4%), a modifiedtechnique was used externalizing the guidewirethrough a sheath percutaneously placed into the leftventricular apex (Figure 2). This was done with theintention of providing coaxiality and support duringTHV deployment in cases where the extreme valveleaflet calcification was thought could prevent coaxialposition. To decrease the risk of embolization, mostoperators made efforts to deploy the valve in aconical shape and flare it in the left ventricle(Figure 3).

Technical success according to MVARC criteria wasachieved in 46 of 64 patients (72%), primarily limited

septal delivery with the guidewire externalized through a sheath

FIGURE 3 Case Example

(A) A mitral valve coplanar view is identified on fluoroscopy to facilitate adequate valve positioning during valve deployment (vertical line of

calcium below the aortic valve). (B) The valve is deployed under rapid pacing and if needed, post-dilated to flare the ventricular side as shown.

(C) The valve was deployed in a 60/40 fashion (60% in the left ventricle and 40% in the left atrium), and mild flare into the left ventricle is

noticeable. (D) Left ventricular angiogram confirms absence of significant mitral regurgitation after transcatheter mitral valve replacement.

J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 9 , N O . 1 3 , 2 0 1 6 Guerrero et al.J U L Y 1 1 , 2 0 1 6 : 1 3 6 1 – 7 1 TMVR for Severe Mitral Annular Calcification

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by the need for a second THV in 11 (17.2%) due tomigration in 5 and regurgitation in 6. After a secondvalve, a stable position was achieved in 57 (89%) pa-tients. At the end of the procedure, the mean MVgradient was 4 � 2.2 mm Hg, while the MV orifice areawas 2.2 � 0.95 cm2. In the 6 patients who required asecond valve due to MR, the mechanism was malpo-sition in 5 patients, either too atrial or too ventricular,preventing adequate seal by the stent frame skirt, andthe sixth case (1.5%) was thought to have a malfunc-tioning leaflet causing severe central MR 3 h after theimplant requiring reintervention with a valve invalve. By the end of the procedure, paravalvularregurgitation was mild or absent in all. There were4 valve embolizations to the left atrium (6.25%), all of

them during the index procedure. Three were treatedwith surgical extraction and 1 was stabilized/trappedin the intra-atrial septum percutaneously with a30 mm Amplatzer Septal Occluder device (St. JudeMedical, St. Paul, Minnesota) in a patient who was nota candidate for surgical rescue.

Six patients (9.3%) had LVOT obstruction withhemodynamic compromise after valve deployment.The average peak LVOT gradient in these patients was72 mm Hg (range 39 to 100 mm Hg). One died while onthe catheterization laboratory table, 1 was stabilizedmedically but died of pneumonia 9 days later, 1 wasconverted to open surgery for valve retrieval and diedhours later, 1 was treated with simultaneous kissingaortic and MV balloon valvuloplasty with significant

FIGURE 4 Procedural Complications and Related 30-Day Mortality

ASA ¼ alcohol septal ablation; BAV ¼ balloon aortic valvuloplasty; BMV ¼ balloon mitral valvuloplasty; LVOT ¼ left ventricular outflow tract;

Med Rx ¼ medical treatment.

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improvement in LVOT gradient but died 48 h later dueto multiorgan failure, and 1 was treated with emergentpercutaneous alcohol septal ablation with resolutionof the gradient and hemodynamic recovery althoughthe patient died 4 days later of complete heart blocksecondary to alcohol septal ablation. Subsequently,1 patient was treated successfully with emergentalcohol septal ablation, improved clinically, and wasdischarged home in stable condition (Figure 4).

There were no cases of annular rupture orperforation reported. The mean length of stay was17.7 � 18 days. Most patients (68.2%) in whomdischarge medication information was available weredischarged on anticoagulation with warfarin plussingle or dual antiplatelet drug.

THIRTY-DAY OUTCOMES. Clinical outcomes are shownin Table 3. The mean follow-up was 4 months (range 1to 34 months). Periprocedural death occurred in 29.7%(19 of 64). A cardiovascular cause was identified in12.5% (8 of 64) and noncardiac in 17.2% (11 of 64). Ofthe 8 cardiovascular deaths, 2 were due to LVOTobstruction, 2 were secondary to left ventricularperforation, 2 were related to ischemic stroke, 1 wasdue to complete atrioventricular block, and 1 was dueto acute myocardial infarction secondary to massiveair embolism in the setting of guidewire-inducedpulmonary vein perforation during a transapical pro-cedure. Of the 11 noncardiac deaths, 5 were attributed

to multiorgan failure, 3 were secondary to pneumonia,2 were due to infection, and 1 was due to bleeding.

Thirty-day follow-up echocardiographic data wereavailable in 22 patients at the time of present anal-ysis. Mean MVG was 5.9 � 2.1 mm Hg (p < 0.0001)with a MVA of 2.3 � 0.8 cm2 (p < 0.0001). Eighteenpatients (81.8%) had zero to trace MR and 4 (18.2%)had mild MR; moderate to severe MR was absent in all(p < 0.0001). The average peak LVOT gradient was15 � 17.8 mm Hg (p ¼ 0.13).

Most survivors reported significant improvementof symptoms. At 30 days, 21 of the 25 patients (84%)with 30-day clinical follow-up data were in NYHAfunctional class I or II, and 4 (16%) in NYHA func-tional class III (p < 0.0001) (Figure 5).

SIMULTANEOUS TMVRANDAORTIC VALVE REPLACEMENT.

Twelve patients (18.7%) underwent concomitantsurgical (5 of 12) or transcatheter (7 of 12) aortic valvereplacement at the index procedure. In the 5 patientswho underwent surgical aortic valve replacement,the SAPIEN XT (3) and SAPIEN 3 (2) were implantedin the native MV via open transatrial approach.When transcatheter aortic valve replacement wasperformed, a transapical approach with Edwardsvalves was selected for all. Thirty-day mortality orcomplication rate was similar in this small subcohort;2 of the 12 patients died within 30 days (25%), 1treated with surgical aortic valve replacement (1 of 3

TABLE 3 Clinical Outcomes

Length of stay, days 17.7 � 18

30-day/procedural death* 19/64 (29.7)

Cardiovascular 8/64 (12.5)

LVOTO 2/64 (3.1)

LV perforation 2/64 (3.1)

Complete AV block 1/64 (1.56)

MI (air emboli due to pulmonary vein perforation) 1/64 (1.56)

Stroke 2/64 (3.1)

Noncardiac 11/64 (17.2)

Multiorgan failure 5/64 (7.8)

Pneumonia 3/64 (4.6)

Thoracentesis related bleeding complication 1/64 (1.56)

Infection 2/64 (3.1)

In-hospital complications

Stroke 4/58 (6.9)

Myocardial Infarction 1/64 (1.6)

Mitral valve reintervention after index procedure 1/64 (1.6)

Major bleeding 14/46 (30.4)

Vascular complication 5/58 (8.6)

New HD requirement 6/58 (10.3)

New permanent pacemaker requirement 8/58 (13.8)

Endocarditis 2/58 (3.5)

Hemolytic anemia 1/58 (1.7)

Valve thrombosis 0/64 (0)

30-day echo

Mean MVG (n ¼ 21) 5.9 � 2.1

MVA (n ¼ 11) 2.3 � 0.8

MR

None to trace 18/22 (81.8)

Mild 2(þ) 4/22 (18.2)

$3(þ) 0/22 (0)

LVOT gradient (n ¼ 12) 15 � 17.8

30-day NYHA functional class

I 7/25 (28)

II 14/25 (56)

III 4/25 (16)

Values are mean � SD or n/N (%). *According to Mitral Valve Academic ResearchConsortium definition.

AV ¼ atrioventricular; HD ¼ hemodialysis; MI ¼ myocardial infarction; NYHA ¼New York Heart Association; other abbreviations as in Tables 1 and 2.

FIGURE 5 NYHA Functional Class at Baseline, 30 Days, and 1 Year Post-Procedure

NYHA ¼ New York Heart Association.

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[30%]) and 1 with transcatheter aortic valve replace-ment (1 of 5 [20%]).

COMPLICATION RATE BY ACCESS TYPE. Thecomplication rate and 30-day mortality were similaramong delivery approaches. However, the highesttechnical success of 88.9% was achieved with thesurgical transatrial approach but the sample size issmall with only 10 patients in this group. Technicalsuccess with the transapical approach was 71.4% and65.4%with transseptal approach. Thirty-daymortalitywas 20% with transatrial approach, 32.1% with trans-apical and 30.7%with antegrade transseptal approach.Valve embolization was seen in 2 transapical cases,1 transseptal and 1 transatrial. LVOT obstruction wasobserved in 3 transapical and 3 transseptal cases. A

second valve was needed in 11 cases (5 transapical, 5transseptal, and 1 transatrial). There was 1 pulmonaryvein perforation in a transapical case and 2 left ven-tricular perforations in the transseptal cases. Conver-sion to open heart surgery was needed in 3 transapicalcases and 1 transseptal procedure.

DISCUSSION

This study is the first large multicenter evaluation ofTMVR with balloon-expandable valves in patientswith severe native MV disease due to severe MAC whowere considered poor candidates for traditional sur-gical MV replacement. We found that TMVR withballoon-expandable valves designed for aortic posi-tion is feasible in this extremely high-risk patientpopulation. Technical success was achieved in mostpatients. Although there were important complica-tions and a high 30-day mortality, these results areencouraging considering this represents the first hu-man experience with a THV not designed for themitral position and used in an extremely high-riskpatient population with a mean Society of ThoracicSurgeons risk score higher than in the PARTNER I(Placement of AoRtic TraNscathetER Valves) trial (13).

The results we report are similar to the complica-tions and mortality reported in the initial experiencewith transcatheter valves designed for the MV totreat patients with MR. In the early experience withthe CardiAQ valve (CardiAQ Valve Technologies,Inc., Edwards Lifesciences), the FORTIS valve(Edwards Lifesciences) and Tiara valve (Neovasc Inc.,

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Richmond, British Columbia, Canada), there werecomplications and several patients died after aseemingly successful procedure (14–18). This mighthave been related to patient selection as some hadsevere left ventricular dysfunction and died of pro-gression of heart failure. It is encouraging that tech-nical success was achieved in the majority of patientsdespite the multiple challenges of the MV anatomyincluding its saddle oval shape, a subvalvular appa-ratus, interaction with the LVOT and aortic valve,and a large size requiring a larger prosthesis, as wellas considering that the balloon-expandable technol-ogy was not designed for the MV and has noanchoring mechanism. It is possible that newerrepositionable and retrievable valve designs might bemore beneficial in this patient population. The use ofthe Lotus valve (Boston Scientific, Marlborough,Massachusetts) and Direct Flow (Direct Flow MedicalInc. Santa Rosa, California) has been reported withsuccess in patients with severe MAC (19,20). Theoption of repositioning or retrieving the valve in thesetting of TMVR-induced LVOT obstruction is animportant advantage over the balloon-expandablevalve technology. One disadvantage is that bothtechnologies have the transapical route as the onlydelivery option at this time.

THE LEARNING CURVE. The learning curve for TMVRin patients with severe MAC has been very steep.There were many unknowns and uncertainties duringthe initial experience of this registry including thebest method for mitral annulus sizing, the amount ofcalcium needed for valve anchoring, the percent ofprosthesis frame oversizing needed for a stable valveposition, and the depth of valve implantation inrelation to the annular plane (how much ventricularand how much atrial). Additional questions included:Can the round-shaped balloon-expandable valve pro-vide adequate seal when implanted in an oval-shapedvalve? Or will it leave a large uncovered space result-ing in significant paravalvular leak? Can embolizationbe predicted or prevented? How to prevent andtreat significant LVOT obstruction post-deployment?What is the optimal valve delivery method? Whichpatients are the best candidates for this technology?This registry provided some answers.

MITRAL ANNULUS SIZING AND THE ROLE OF IMAGING.

In the absence of a validated standard method formitral annulus sizing, operators have extrapolatedfrom TAVR experience and used a variety of sizingapproaches including echocardiography, 3D trans-esophageal echocardiography, cardiac CT, and balloonsizing techniques. Only few patients treated in theearly experience were not evaluated with cardiac CT.

However, this imaging modality rapidly became themost accepted method for annulus sizing. It was soonrecognized that CT may also provide essential infor-mation for pre-procedural planning. It helps evaluatethe amount and distribution of calcium in an attemptto predict valve anchoring and features that may assistin predicting LVOT obstruction including the aorto-mitral angle, the anterior leaflet length, the size of theleft ventricular cavity, the presence of septal hyper-trophy, and the change in the residual LVOT space inrelation with the depth of valve implantation. It canalso be helpful in planning the site and trajectoryof transapical or transseptal access (Figure 1).

PATIENT SELECTION. Most of the procedural deathswere noncardiac. The registry’s patient population hadan extremely high-risk profile and some were perhapstreated too late in their disease process, similar tothe so-called “cohort C” patients in the transcatheteraortic valve replacement experience. As the operatorslearned about annulus sizing, LVOT obstruction riskassessment, anchorage prediction assessment andbetter patient selection, there was a decreased rateof major cardiac complications and overall mortality.

STUDY LIMITATIONS. This study has important limi-tations inherent to registries. The total number of pa-tients analyzed is small and most centers includedonly 1 or 2 patients. Because this is real-world practiceexperience, the patient population is not homoge-neous. Most of the data were collected retrospectively,and not all data were captured or reported in all cen-ters, resulting in significant amount of missing data.The clinical outcomes were self-reported. Becausethe clinical events were not adjudicated, it is possiblethat the adverse events were underestimated. Inaddition, there were no core laboratories utilized. Thisis a new procedure and most patients were treatedfairly recently. Therefore, 1-year or longer follow-upwas available in a small number of patients and dura-bility and long-term outcomes are yet unknown.

NEED FOR A CLINICAL TRIAL. A prospective clinicaltrial may help overcome the important limitations ofthis registry. The MITRAL (Mitral Implantation ofTRAnscatheter vaLves) trial (NCT02370511) is anFood and Drug Administration–approved physician-sponsored pilot Investigational Device Exemptiontrial that is currently ongoing in the United States tosystematically evaluate the safety and feasibility ofthis technology in severe native MV disease with se-vere MAC. We anticipate that the MITRAL trial willhelp provide insights to further improve technicalsuccess, patient selection, and the overall clinicaloutcomes of this patient population.

PERSPECTIVES

WHAT IS KNOWN? Patients with severe MAC have very high

surgical risk for standard MV surgery. There is currently an unmet

clinical need for many patients who are not treated due to their

high surgical risk. There is limited data from few isolated reports of

successful TMVR with balloon-expandable aortic THVs in patients

with MAC who are not candidates for standard surgery.

WHAT IS NEW? This is the largest multicenter report to date of

patients with severe MAC undergoing TMVR.We found that TMVR

is feasible in patients with severe MAC who are not candidates for

standard MV surgery but is associated with significant adverse

events.

WHAT IS NEXT? Further studies are needed to refine the

screening process to improve outcomes. The MITRAL trial is

prospectively evaluating the safety and feasibility of this proce-

dure and may provide further insights to improve the technical

success, patient selection, and overall clinical outcomes.

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CONCLUSIONS

This first multicenter registry report of TMVR withballoon-expandable valves in patients with severeMAC demonstrates that the procedure is feasible butmay be associated with significant adverse events.This strategy might be an alternative for selected high-risk or inoperable patients with limited treatment op-tions, but remains off-label at this time. Furtherstudies are needed to refine the screening process toimprove outcomes of this challenging procedure.

ACKNOWLEDGEMENT The authors wish to thankYing Zhou for the statistical analysis support pro-vided in the preparation of this manuscript.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Mayra Guerrero, Director of Cardiac Structural In-terventions, Evanston Hospital/NorthShore Univer-sity Health System, 2650 Ridge Avenue, WalgreenBuilding, 3rd Floor, Evanston, Illinois 60201. E-mail:mguerrero@northshore.org.

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KEY WORDS calcific mitral stenosis, mitralannular calcification, mitral valve disease,mitral valve replacement, transcathetervalve replacement

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