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Severe Mitral Regurgitation:

Device or Surgery?

Bernard Iung - Hôpital Bichat, Paris

Kardiologie Update – 30th November 2014

Bernard Iung, MD, 2014

Consultancy:

• Abbott

• Boehringer Ingelheim

• Valtech

Speaker’s fee

• Edwards Lifesciences

Disclosures

Prevalence of Mitral Regurgitation

11 911 randomly selected 2881 patients from the

patients with echo Framingham cohort

(Nkomo et al. Lancet 2006;368:1005-11) (Singh et al. Am J Cardiol 1999;83:897-902)

Primary MR

(or Organic MR)

Secondary MR

(or Functional MR)

Valve structure Abnormal Normal

Mechanism Primary valve / subvalvular

lesion

Distortion of the valvular

apparatus due to LV

remodelling

Causes Degenerative / Rheumatic

/ Endocarditis / Other

Ischaemic heart disease

/ Cardiomyopathy

LV dysfunction Consequence Cause

Primary / Secondary MR

Primary MR

3491 patients from the Framingham cohort

• 2.4% had mitral valve prolapse • Mitral regurgitation was severe in 3.5% of them

(Freed et al. N Engl J Med 1999;341:1-7)

• Aetiologies of MR in the Euro Heart Survey (877 patients with MR)

• Prevalence of degenerative mitral regurgitation

7%

9%

4%

5%

14% 61%

Degenerative

Rheumatic

Congenital

Endocarditis

Other

Ischaemic

www.escardio.org/guidelines

Class Level

Mitral valve repair should be the preferred technique when it is expected to be

durable. I C

Surgery is indicated in symptomatic patients with LVEF > 30% and LVESD

< 55 mm. I B

Surgery should be considered in patients with severe LV dysfunction

(LVEF < 30% and/or LVESD > 55 mm) refractory to medical therapy with high

likelihood of durable repair and low comorbidity.

IIa C

Surgery may be considered in patients with severe LV dysfunction (LVEF < 30%

and/or LVESD > 55 mm) refractory to medical therapy with low likelihood of

durable repair and low comorbidity.

IIb C

Indications for surgery in symptomatic severe primary MR

Eur Heart J 2012;33:2451-296

Eur J Cardiothorac Surg 2012;42:S1-S44

www.escardio.org/guidelines

Operative mortality after surgery for MR

Eur Heart J 2012;33:2451-296

Eur J Cardiothorac Surg 2012;42:S1-S44

47 279 patients aged ≥ 75 undergoing isolated mitral valve surgery

between 2000 and 2009 (replacement in 29 919, repair in 17 360)

(Vassileva et al. Circulation 2013;127:1870-6)

Late Survival after Surgery for MR

Flail gap Flail width

(Feldman T et al JACC 2009; 54 :686-94)

MitraClip® for Primary MR

Device (%) n=184

Control (%) n=95

P

Age (mean) 67.3 years 65.7 years 0.32

Male 62.5 66.3 0.60

Congestive heart failure 90.8 77.9 <0.01

Coronary artery disease 47.0 46.3 >0.99

Myocardial infarction 21.9 21.3 >0.99

Angina 31.9 22.2 0.12

Atrial fibrillation 33.7 39.3 0.42

Cerebrovascular disease 7.6 5.3 0.62

Peripheral vascular disease 6.5 11.6 0.17

Cardiomyopathy 17.9 14.7 0.61

Hypercholesterolemia 61.0 62.8 0.80

Hypertension 72.3 78.9 0.25

Moderate to severe renal disease 3.3 2.1 0.72

Diabetes 7.6 10.5 0.50

Previous cardiovascular surgery 22.3 18.9 0.54

MR Severity: 3+ to 4+ 95.7 92.6 0.48

MR Etiology: Degenerative / Functional 73 / 27 73 / 27 0.81

EVEREST II Randomized Clinical Trial Baseline Demographics & Co-morbidities

(Feldman et al. N Engl J Med 2011;364:1395-1406 )

• 117 pts with severe degenerative MR

Mean Euroscore 15±13% (≥ 20% in 33 pts)

• 30-day mortality 6.0%

• 81% NYHA I-II at 1 yr. (26% before the procedure)

(Reichenspurner et al. Eur J Cardiothorac Surg 2013;44:e280-8)

MitraClip® for Primary MR: ACCESS EU

www.escardio.org/guidelines

Percutaneous techniques

● Percutaneous edge-to-edge procedure may be

considered in patients with symptomatic severe primary

MR who fulfill the echo criteria of eligibility, are judged

inoperable or at high surgical risk by a ‘heart team’,

and have a life expectancy greater than 1 year

(Class IIb Level C)

Eur Heart J 2012;33:2451-296

Eur J Cardiothorac Surg 2012;42:S1-S44

European Society of Cardiology – Euro Heart Survey

Severe Symptomatic MR

Isolated MR

(n=877)

No Severe MR

(n=331)

Severe MR

(n=546)

No Symptoms

n=144

Symptoms

n=396

Intervention

n=203 (51%)

No Intervention

n=193 (49%)

Symptoms

missing

n=6

Severe MR : ≥ 3/4 at Doppler-echocardiography

Symptomatic MR : NYHA Class II or greater

(Mirabel et al. Eur Heart J 2007;28:1358-65)

European Society of Cardiology – Euro Heart Survey

Total No Intervention Intervention

All aetiologies 396 193 203

EuroSCORE, m±SD 12.5±14.6 16.7±17.1 8.6±10.3*

EuroSCORE ≥ 20, n(%) 70 (18%) 50 (26%) 20 (10%)*

Degenerative MR 209 117 92

EuroSCORE, m±SD 14.7±15.4 18.7±17.8 9.6±9.7*

EuroSCORE ≥ 20, n(%) 47 (23%) 37 (32%) 10 (11%)†

Decision to Operate and Risk Score

* p<0.0001

† p<0.001

Secondary Mitral Regurgitation

MR

WORSE MR VOLUME OVERLOAD

LV DILATION

(Levine et al. Curr Cardiol Rep 2002;4:125-9)

www.escardio.org/guidelines

Indications for mitral valve surgery in secondary mitral regurgitation

Class Level

Surgery is indicated in patients with severe MR undergoing CABG, and

LVEF > 30%. I C

Surgery should be considered in patients with moderate MR undergoing

CABG*. IIa C

Surgery should be considered in symptomatic patients with severe MR,

LVEF < 30%, option for revascularization, and evidence of viability. IIa C

Surgery may be considered in patients with severe MR, LVEF > 30%,

who remain symptomatic despite optimal medical management

(including CRT if indicated) and have low comorbidity, when

revascularization is not indicated.

IIb C

* Exercise echo is recommended to identify dyspnea, increase in severity of MR and in SPAP

Eur Heart J 2012;33:2451-296

Eur J Cardiothorac Surg 2012;42:S1-S44

www.escardio.org/guidelines

Background in the Management

(Moderate-Severe) Secondary MR

1. Operative mortality is higher than in primary MR

2. Long-term prognosis is worse (comorbidities)

3. No evidence that surgery prolongs life (5-yrs death 50%)

1. CABG alone does not correct MR in most patients

2. Untreated MR is associated with recurrent HF and death

3. Functional improvement uniformly reported after MVS

4. Persistence and high recurrence rate of MR after MV repair

Non randomized observational

trials for most

Retrospective trials

One randomized study not powered to evaluate the outcome has compared

CABG with CABG/MVRepair in moderate ischaemic MR

Improvement in class/LV function (Fattouch et al. JTCS 2009;138:278-85)

• 301 pts with multivessel CAD and ischaemic MR

(ERO 0.2 to 0.4 cm², vena contracta 3 to 7 mm)

• Randomized to CABG + valve repair vs. CABG

• LVESVI at 1 yr: 49.6±31.5 ml (CABG+MVR) vs.46.1±22.4 ml/m² (CABG alone) (p=0.61)

(Smith et al. N Engl J Med 2014;Nov.18)

Surgery for Ischaemic MR

• 251 pts with severe ischaemic MR (ERO >0.4 cm²)

• Randomized to valve repair or replacement ± CABG

• LVESVI at 1 yr: 61.1±26.2 ml/m² (repair) vs. 65.7±27.4 ml/m² (replacement) (p=0.18)

(Acker et al. N Engl J Med 2014;370:23-32)

Repair / Replacement for Ischaemic MR

•

(Feldman T et al JACC 2009; 54 :686-94)

Coaptation length Coaptation depth

MitraClip® for Secondary MR

ACCESS EUROPE Registry

EVEREST II RCT Device Patients

N=178

ACCESS EU MitraClip Patients

N=567

Age (yrs), mean±SD 67 ± 13 74 ± 10

Logistic EuroSCORE, (%)

Mean ± SD NA 23 ± 18

EuroSCORE ≥ 20% (%) NA 45

Coronary Artery Disease (%) 47 63

NYHA Functional Class III or IV (%) 50 85

Mitral Regurgitation Grade ≥3/4 (%) 96 98

Ejection Fraction < 40% (%) 6 53

Secondary MR (%) 27 77

Ischaemic NA 42

Non-ischaemic NA 58

Degenerative MR (%) 73 23

(Maisano et al. J Am Coll Cardiol 2013;62:1052-61)

ACCESS EUROPE Registry

• Mortality

− 3.4% at 30 days

− 17.3% at 1 year

• Mitral regurgitation

• Functional class 71.4% NYHA I-II at 1 year (15.1% before the procedure)

(Maisano et al. J Am Coll Cardiol 2013;62:1052-61)

EVEREST High-Risk + REALISM

N=351

Age (yrs), mean±SD 76 ± 10

STS score (%) 11.3 ± 7.7

STS > 12% (%) 43

Coronary Artery Disease (%) 82

NYHA Functional Class III or IV (%) 85

Mitral Regurgitation Grade ≥3/4 (%) 100

Ejection Fraction < 40% (%) 47 ±1 4

Secondary MR (%) 70

Degenerative MR (%) 30

• MR ≥ 3/4

• and high-risk: STS ≥ 12 % or predefined comorbidity

(Glower et al. J Am Coll Cardiol 2014;64:172–81)

MitraClip® in High-Risk Patients

• Mortality

− 4.8% at 30 days

− 22.8% at 1 year

• Late survival MR grade (223 pts)

(Glower et al. J Am Coll Cardiol 2014;64:172–81)

MitraClip® in High-Risk Patients

www.escardio.org/guidelines

Percutaneous techniques

● The percutaneous mitral clip procedure may be considered

in patients with symptomatic severe secondary MR despite

optimal medical therapy (including CRT if indicated), who

fulfil the echo criteria of eligibility, are judged inoperable or

at high surgical risk by a team of cardiologists and cardiac

surgeons, and who have a life expectancy > 1 year

(Class IIb Level C)

“These findings have to be confirmed in larger series

with longer follow-up and with a randomized design”

Eur Heart J 2012;33:2451-296

Eur J Cardiothorac Surg 2012;42:S1-S44

Optimal Valve morphology

Central pathology in segment 2

No leaflet calcification

Mitral valve opening area >4cm²

Mobile length of the posterior leaflet ≥10mm

Coaption depth <11mm

Normal leaflet strength and mobility

Flail-width <15mm Flail-gap <10mm

(Boekstegers et al. Clin Res Cardiol 2014;103:85–96)

Anatomy and Patient Selection

Ideal morphologies for a MitraClip implantation

(Wunderlich and Siegel. Eur Heart J Cardiovasc Imag 2013;14:935-9)

Conditionally suitable valve morphology

Pathology in segment 1 or 3

Mild calcification outside of the grip-zone of the clip system; ring

calcification, post annuloplasty

Mitral valve opening area >3cm² with good residual mobility

Mobile length of the posterior leaflet 7-<10mm

Coaption depth ≥11mm

Leaflet restriction in systole (Carpentier IIIB)

Flail-width >15mm only with a large ring width and the option for

multiple clips

Only in experienced centres

(Boekstegers et al. Clin Res Cardiol 2014;103:85–96)

Anatomy and Patient Selection

(Boekstegers et al. Clin Res Cardiol 2014;103:85–96)

Unsuitable valve morphology

Perforated mitral valve leaflet or cleft

Severe calcification in the grip-zone

Haemodynamically significant mitral stenosis (valve opening

area <3cm², MPG ≥5mmHg)

Mobile length of the posterior leaflet <7mm

Rheumatic leaflet thickening and restriction in systole and

diastole (Carpentier IIIA)

Barlow’s syndrome with multisegment flail leaflets

Anatomy and Patient Selection

Unsuitable morphologies for a

MitraClip implantation

Large Commissural

prolapse

Severe Bivalvular

prolapse

Bichat

Bichat

• MR is frequent and represents a significant burden in the

elderly.

• Surgery remains the reference treatment of primary MR.

• Approximately half of patients with severe, symptomatic

MR are denied surgery.

• High-risk patients (EuroSCORE ≥ 20) account for 1 out of

4 patients with degenerative severe MR and 1 out 3 of

those denied for surgery.

• Percutaneous techniques can be used in less favourable

anatomical conditions.

Conclusion (I)

• Indications for surgery are more restrictive for secondary

mitral regurgitation.

• The availability of lower-risk procedures is of particular

interest for secondary MR.

• Preliminary results of percutaneous interventions are

promising, but randomized trials are needed (and ongoing).

• Prospective population-based studies are also needed to

assess the number of potential candidates for

percutaneous techniques.

Conclusion (II)

251 high-risk patients

with severe MR

-139 transcatheter

-53 surgical

-59 conservative

(Swaan et al.

J Am Coll Cardiol Intv

2014;7:875–81)

(Swaan et al. J Am Coll Cardiol Intv 2014;7:875–81)

Propensity analysis vs. conservative therapy

-Transcatheter HR 0.41 |0.22-0.78], p=0.006

-Surgery HR 0.52 [0.30-0.88], p=0.014

Temporal Changes in

MitraClip indication

4932

www.escardio.org/guidelines

Echocardiographic criteria for the definition of severe valve regurgitation: an integrative approach

Aortic regurgitation Mitral regurgitation Tricuspid

regurgitation

Qualitative

Valve

morphology

Abnormal/flail/large

coaptation defect

Flail leaflet/ruptured papillary

muscle/large coaptation defect

Abnormal/flail/large

coaptation defect

Colour flow

regurgitant jet

Large in central jets,

variable in eccentric jets

Very large central jet or

eccentric jet adhering, swirling,

and reaching the posterior wall

of the left atrium

Very large central jet or

eccentric wall impinging

jet

CW signal of

regurgitant jet

Dense Dense/triangular Dense/triangular with

early peaking (peak vel

< 2 m/s in massive TR)

Other Holodiastolic flow reversal

in descending aorta

(EDV > 20 cm/s)

Large flow convergence zone –

Adapted from Lancellotti, EAE Recommendations. Eur J Echocardiogr. 2010;11:223-244 and 307-332

Eur Heart J 2012;33:2451-296

Eur J Cardiothorac Surg 2012;42:S1-S44

www.escardio.org/guidelines

Aortic regurgitation

Mitral regurgitation Tricuspid

regurgitation

Semiquantitative

Vena contracta width (mm)

> 6 ≥ 7 (> 8 for biplane) ≥ 7

Upstream vein flow – Systolic pulmonary vein flow reversal

Systolic hepatic vein flow reversal

Inflow – E-wave dominant ≥ 1.5 m/s E-wave dominant ≥ 1 m/s

Other Pressure half-time < 200 ms

TVI mitral/TVI aortic > 1.4 PISA radius > 9 mm

Quantitative Primary Secondary

EROA (mm²) ≥ 30 ≥ 40 ≥ 20 ≥ 40

R Vol (ml/beat) ≥ 60 ≥ 60 ≥ 30 ≥ 45

+ enlargement of cardiac chambers/ vessels

LV LV, LA RV, RA, inferior vena cava

Echocardiographic criteria for the definition of severe valve regurgitation: an integrative approach

Adapted from Lancellotti, EAE recommendations. Eur J Echocardiogr. 2010;11:223-244 and 307-332

Eur Heart J 2012;33:2451-296

Eur J Cardiothorac Surg 2012;42:S1-S44

Ischaemic MR After MI

Community-Based Study

• 773 patients undergoing echocardiography within 30 days

following myocardial infarction (mean 3 days)

− 50% ≥ mild MR

− 12% moderate or severe MR

• Ischaemic MR was a predictor of death in multivariate

analysis: adjusted HR 1.55 [1.08-2.22] p=0.019

(Bursi et al. Circulation 2005;111:295-301)

• But subject to changes with LV remodelling

Prevalence of Secondary MR in Chronic

Heart Failure with Impaired LVEF

n= Age

(yrs)

LVEF

(%)

Ischaemic

Dis. (%)

MR Severity

Varadarajan

(JASE 2006)

370 65 21 94 15% grade 3/4

14% grade 4/4

Rossi

(Heart 2011)

1256 67 32 73 24% ERO ≥0.20 cm²

or Reg.vol >30 ml

Agricola (Int J

Cardiol 2011)

198 66 33 65 50% ERO ≥0.20 cm²

Bursi (Eur J

Heart Fail 2010)

469 60 30 95 30% grade 3/4

14% grade 4/4

Deja

(Circulation 2012)

1212 60 27 64 18% moderate or

severe

Estimated Burden of Secondary MR

• ≥ 20% of severe secondary MR in patients with chronic

heart failure due to ischaemic or non-ischaemic

cardiomyopathy

• Estimation of 6 million adults with heart failure in the US,

with 45% of them due to LV dysfunction (Bursi et al. JAMA 2006;296:2209-16)

(Go et al. Circulation 2013;127:e6-e245)

• Estimation of ≥ 500 000 adults with chronic severe

secondary MR in the US

© 2014 Abbott. All rights reserved. AP2939842-OUS Rev. C (08/2014) - 9-EH-4-3874-01 08-2014 REV H

48 Information contained herein intended for use in EMEA

*Data as of 31/7/2014. Source: Abbott Vascular

Study Population N*

EVEREST I (Feasibility) Feasibility patients 55

EVEREST II (Pivotal) Pre-randomized patients 60

EVEREST II (Pivotal) Non-randomized patients

(High Risk Study)

78

EVEREST II (Pivotal) Randomized patients

(2:1 Clip to Surgery)

279

184 Clip

95 Surgery

REALISM (Continued Access) Non-randomized patients 899

Compassionate/Emergency Use Non-randomized patients 66

ACCESS Europe Phase I Non-randomized patients 567

ACCESS Europe Phase II Non-randomized patients 286

Commercial Use Commercial patients 13,738

Total 15,933

+95 surgery

Worldwide Experience in July 2014

Commercial Investigational Special Access

1. First-time procedures only. Includes commercial patients, ACCESS I and ACCESS II patients.

2. Successful implants only. Includes commercial patients, ACCESS I and ACCESS II patients.

3. Successful implants only.

MitraClip Therapy Current Global Adoption

Treating Centers 219

Patients (clinical and real-

world) 6,839

Patients1 (real-world) 5,644

Implant Rate2 96%

Acute MR reduction2,3 98% of

implants

Functional MR2 67%

Degenerative MR2 24%

Mixed2 9%

Mitraclip therapy

Combination of

Techniques

Transcatheter Mitral Valve Implantation

EndoValve CardiAQ( n=3) Medtronic

Neovasc – Tiara( n=3) Lutter Valve (n=2)

Challenges Positioning Fixation Paravalvular leaks Valve gradient and LV outflow track obstruction Thrombosis Durability Feasibility of reintervention …….

Fortis (n=8)

(Lubos et al. J Am Coll Cardiol Intv 2014;7:394–402)

300 high risk patients unsuccessfully treated (discharge MR grade of >2)

a TMPG ≥4 mm Hg, an EROA >70.8 mm2, and an MVOA < 3.0 cm2 carry an

increased risk of acute procedural failure

European Society of Cardiology – Euro Heart Survey

Factors Associated with a Decision

not to Operate on Symptomatic MR

p OR [95% CI]

LV ejection fraction (per 10% decrease)

0.0002 1.39 [1.17 – 1.66]

Aetiology Ischemic Non-ischemic

0.0006 1

4.44 [1.96 – 10.76]

Age (per 10-year increase)

0.001 1.40 [1.15 – 1.72]

Charlson comorbidity index (per 1 point increase)

0.004 1.38 [1.12 – 1.72]

Degree of MR Grade 4/4 Grade 3/4

0.005 1

2.23 [1.28-3.29]

(Mirabel et al. Eur Heart J 2007;28:1358-65)

ACC/AHA Recommendations for

chronic primary MR

Recommendations COR LOE

Transcatheter mitral valve repair may be considered

for severely symptomatic patients with chronic

severe primary MR who have a reasonable life

expectancy but a prohibitive surgical risk because

of severe comorbidities

IIb

B

Nishimura et al. 2014 AHA/ACC Guideline for the Management of Patients

With Valvular Heart Disease. Circulation 2014;129:e521-643

Unsuitable morphologies for a MitraClip implantation

(Wunderlich and Siegel. Eur Heart J Cardiovasc Imag 2013;14:935-9)

• MR grade (223 pts)

• Functional class

(233 pts)

(Glower et al. J Am Coll Cardiol 2014;64:172–81)

MitraClip® in High-Risk Patients