07/02/2018

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Percutane behandeling van mitralisklepinsufficientie:Adding Years to Life and Life to Years?!

Martin Swaans, MD, PhD

CardioloogSt.Antonius ziekenhuis Nieuwegein

• Grant/Research Support

• Consulting Fees/Honoraria

• Major Stock Shareholder/Equity

• Royalty Income

• Ownership/Founder

• Intellectual Property Rights

• Other Financial Benefit

Disclosure Statement of Financial Interest

• None

• Abbott Vascular, Philips,

Boston Scientific

• None

• None

• None

• None

• None

Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.

Affiliation/Financial Relationship Company

Mitral Regurgitation

• Mitral regurgitation (MR) is the second most common type of heart valve disease needing surgery in Europe

• Controversy regarding optimal timing of intervention in asymptomatic patients with severe MR, consensus in symptomatic patients

• Poor prognosis in absence of surgery

• Even with optimal medical therapy (OMT)

Pre

vale

nce (%

) o

f m

od

era

te to

se

ve

re v

alv

e d

ise

ase

<45 45–54 55–64 65–74 >75Age (years)

Prevalence of valvular heart disease by age

Prevalence of Valvular Disease Increases with Age

Source: Nkomo VT, et al. Lancet. 2006;368:1005-11.

All valve diseaseMitral valve diseaseAortic valve disease

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As mitral regurgitation becomes more severe, morbidity and mortality risk increases

• Poor quality of life

• Repeat hospitalisations

Agricola E et al. Eur J Heart Fail 2009;11:581–7.

Event – free survival decreases

with increasing MR severity

Days

Tra

nspla

nt-

free s

urv

ival

(%)

P<0.0001

Risk of mortality increases

with increasing NYHA class

Cum

ula

tive

ris

k o

f all-

cause m

ort

alit

y (%

)

Long run test p<0.001 Follow-up in months

Cioffi G et al. European Journal of Heart Failure 2005

Mitral regurgitation (MR) progresses to Heart Failure

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Anterior annulus Anterior leaflet

Chordae tendineae

Posterior leaflet

Posterior annulus

Medial papillary muscle

Lateral papillary muscle

The Mitral Valve Anatomy

The leaflets are normally asymmetric—the

anterior leaflet has a larger surface area, but occupies a smaller amount of annular

circumference.

Images modified from Carpentier, A. et al. Carpentier’s Reconstructive Valve Surgery. Saunders Elsevier; 2010.

The mitral valve apparatus includes

the annulus, the leaflets, the chordae tendineae, and papillary muscles.

Posterior leaflet

Anterior leaflet

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Mitral regurgitation: morphologic classification

• Primary MR, also known as degenerative MR (DMR) or organic MR– refers to an anatomic defect of one or more structures comprising

the mitral valve apparatus

• Secondary MR, also known as functional MR (FMR)– Result of left ventricular (LV) dysfunction and dilation, which

causes otherwise normal valve components to fail and produce MR

Normal Mitral Valve DMR - Prolapse DMR - Ruptured Chordae FMR

Classification of MR – Primary MR Classification of MR – Secondary MR

MV-surgery in MR

High-risk MV-surgery

• Symptomatic patients with a severe MR have a class I recommendation for surgery

• Up to 50% of patients are not referred to surgery

• Even higher when accompanied by heart failure

• Operative risk not negligible!

• In-hospital mortality ranges between 5-10%, up to 25% in high risk patients

• High rates of residual or recurrent MR

Iung B et al. The Euro Heart Survey on Valvular Heart Disease. Eur Heart J 2003;24:1231–43.

Goel SS et al. J Am Coll Cardiol 2014;63:185-6

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Residual / recurrent MR > 2+ after undersized annuloplasty

Magne et al. Cardiology 2009;112:244.

Residual or recurrent MR worsensprognosis

De Bonis M et al. Ann Thorac Surg 2008;85:932-9McGee EC et al. JTCVS 2004;128:916-24

Mihaljevic et al. J Am Coll Cardiol 2007;49:2191-201Crabtree TD et al. Ann Thorac Surg 2008;85:1537-43

• Recurrence of MR also parallels the absence of LV-remodeling

No Mortality Benefit!

Wu AH et al. JACC 2005

MitraClip a solution?

MitraClip system Animation

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Experienced centres can treat more

complex patients

Large

Flail gap

> 15mm

Experienced centres can treat more complex patients

Pathology

not in

A2/P2

Importance of echo screening on treatment strategy

Pathology not in A2/P2,

No coaptation

Pre-procedure Post-procedure

LVOT

2CH

PGmean:4.6 mmHg

Is MitraClip a solution?

• Surgical treatment of FMR is associated with

– High hospital mortality (up to 25%)

– High recurrence rate

– Long hospital stay

– Unproven survival benefit

• Mitraclip for FMR

– Procedure more simple than for DMR

– Improvement of symptoms at low risk

– Failure does not modify the surgical option

– Improve symptoms and quality of life

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Factors prohibiting

surgery include6:

• Impaired LVEF

• High operative risk

• Multiple comorbidities

• Advanced age

Of surgical candidates,

up to 50% of patients

are not referred to surgery, even if a

surgical indicationexists 2

An unmet need: Patient with MR ≥ 3+ (DMR & FMR)

Large portion of patients with moderate-to severe and severe mitral regurgitation patients are left untreated -ineligible for surgical

treatment or denied surgical intervention1-2

49%High-Risk

Patients3-5

49%Surgical

Candidates

2%Surgical Patients

1. Iung B, et al. Eur Heart J. 2003;24:1231-1243.

2. Mirabel M, et al. Eur Heart J. 2007;28:1358-1365.

3. U.S. Census Bureau, Statistical Abstract of the U.S.

4. Nkomo et al. Burden of Valvular Heart Diseases: A Population-based Study, Lancet, 2006; 368: 1005-11.

5. Patel, et al. Mitral Regurgitation in Patients with Advanced Systolic Heart Failure, J of Cardiac Failure, 2004.

6. Rankin, et al, J of Thoracic and Cardiovascular Surgery, March 2006

MitraClip therapyProcedural success

• High rate of acute procedural success

(achieved MR reduction of grade 2+ or less)

1. F. Maisano, et al., Journal of the American College of Cardiology 62, 1052 (2013)/ 2.W. Schillinger, et al., EuroIntervention : journal of EuroPCR

in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 9, 84 (2013)/3. C. Grasso, et al., The American journal of cardiology 111, 1482 (2013) / 4.X.

Armoiry, et al., Archives of cardiovascular diseases 106, 287 (2013)

ACCESS EU1 TRAMI2 GRASP3 French4

91.2% 95.3% 100% 95.2%

MitraClip therapy: Safety profile

Low Major Adverse Events (MAEs)

0% 10% 20% 30% 40% 50% 60%

EVEREST II RCT

EVEREST II HSR

REALISM

TRAMI HRS

GRASP

Surgery

MitraClip

1. T. Feldman, et al., The New England journal of medicine 364, 1395 (2011)/ 2. P. L. Whitlow, et al., Journal of the American College of Cardiology 59, 130 (2012)/ 3. F. Maisano, et al., Journal of the American College of Cardiology 62, 1052 (2013)/ 4. S. Kar, Presented

at TCT, 20 13, San Francisco, CA (2013)/ 5. W. Schillinger, et al., EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 9, 84 (2013)/4. C. Grasso, et al., The American journal

of cardiology 111, 1482 (2013)

Low post-procedural mortality

• Minimally invasive procedure

• Beating heart procedure - no cardiopulmonary bypass

0% 2% 4% 6% 8% 10%

30days

30days

30days

30days

HRS

LRS

30days

EV

ER

ES

T

II R

CT

EV

ER

ES

T

II H

SR

RE

AL

ISM

AC

CE

SS

TR

AM

IG

RA

SP

Mit

raC

lip

Mit

ral

Valv

e S

urg

ery

MitraClip therapy Durable clinical outcomes

Sustained NYHA Class improvement at 5 years1 - NYHA Functional Class at Baseline, 1 year and 5 year

0

10

20

30

40

50

60

70

80

90

100

BL 1 Year BL 5 Year

I

II

III

IV

0

10

20

30

40

50

60

70

80

90

100

BL 1 Year BL 5 Year

98% 91% 88% 91%

N=151 N=106 N=66 N=42

1. EVEREST II 5 years presentated by T. Feldman at ACC 2014

0

10

20

30

40

50

60

70

80

90

100

BL 1 Year BL 5 Year

0+

1+

2+

3+

4+

N=149 N=106

0

10

20

30

40

50

60

70

80

90

100

BL 1 Year BL 5 Year

N=66 N=41

Mit

raC

lip

81% 82% 99% 98%

Mit

ral

Valv

e S

urg

ery

Sustained MR Reduction at 5 years1 - MR Severity at Baseline, at 1 year and 5 year

MitraClip therapy Durable clinical outcomes

Sustained reverse remodeling of the LV at 1 year and 5 years

EVEREST ll High-Risk – LV Remodeling at 1 and 5 Years

Paired data (N=153)

132,6

120,8

100

120

140

Vo

lum

e (m

l)

Baseline 1 Year

-11.9 mLp<0.05

Left Ventricular End

Systolic Volume

Paired data (N=153)

60,0

57,9

55

60

65

Baseline 1 Year

-2.2 mLp<0.05

Left Ventricular End

Diastolic Volume

REALISM Non-High Risk - 1 Year Outcomes

N=54 ; p<0.0001

-32.1

N=54 ; p<0.005

-10.0

LVEDV (mL) at 1 Year

LVESV (mL) at 1 Year

-100 -80 -60 -40 -20 0 20

N=24 ; p<0.0001

N=24 ; p<0.05

-38.2

-14.6

LVEDV (mL) at 5 Years

LVESV (mL) at 5 Years

• EVEREST ll High-Risk 5 Years Outcomes – reverse LV remodeling demonstrated by reduction in LVEDV and LVESV

• REALISM Non-High Risk 1 Year Outcomes - significant improvements in LV dimensions indicating reverse remodeling

S. Kar, EII High-Risk , ACC 2014 S. Kar, S. Lim, REALISM Non-High Risk , ACC 2013

MitraClip therapy

0 2 4 6 8 10

EII RCT

REALISM

EU Sentinel (TAVI)

TAVI

Surgery

MitraClip

1. C.Di Mario (Eurointervention 2012) 2. T. Feldman, et al., The New England journal of medicine 364, 1395 (2011) 3. S. Kar, et al., Journal of the American College of Cardiology 61, E1959 (2013) 4. M Gillard

(NEJM 2012) 5. Lim EVEREST II High-Risk DMR TCT 2012 6. Wiebe J., et al., Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions (2014).

Short length of stay1,2&3 Short ICU stay 2,3,4&5

Most of patients are discharged directly at home6

Stay of patients after termination of mitral valve therapy in different age groups of patients are similar.

Regular discharge 82%

Internal transfer 2%

Other hospital 5%

Rehab hospital 9%

Nursing home 2%

≥ 7

6 Y

EA

RS

0 1 2 3 4 5 6

EVEREST II HSR (DMR)

REALISM

France 2

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Adding Years to Life and Life to Years?!

(N=264, matched cases)

13.5 pointsMean improvement

Minnesota Living With Heart Failure Questionnaire

p<0.0001

Functional Improvement in 6-Minute Walk Test

275334

0

100

200

300

400

Baseline 1 Year

Me

ters

Wa

lke

d

+59.5m

improvement

p<0.0001

(N=216, matched cases)

Schillinger et al. ACCESS EU – 1 Yr. ESC 2012

MitraClip therapyImproves quality of life

MitraClip therapyReduction in recurrent hospitalization rate

• Reduction of recurrent hospitalization rate in High surgical risk patients

0

0,2

0,4

0,6

0,8

1

1 Year Prior to MitraClip 1 Year Post MitraClip

EVEREST II

High Surgical Risk

Functional MR Patients

EVEREST II

High Surgical Risk

Degenerative MR Patients

An

nu

al

rate

of

CH

F H

os

pit

ali

sa

tio

ns

(CH

Ho

sp

ita

lis

ati

on

sP

er

Pa

tie

nt-

Ye

ar)

0.65

0.29

(N=110, matched Site Assessed)

0

0,2

0,4

0,6

0,8

1

1 Year Prior to

MitraClip

1 Year Post MitraClip

(N=42, matched)

0.74

0.17

55% Reduction

P < 0.00173% Reduction

P < 0.001

Feldman, T. EVEREST II High Surgical Risk Cohort: Effectiveness of Percutaneous Reduction of Significant Mitral Regurgitation in Degenerative Etiology. Transcatheter

Cardiovascular Therapeutics Annual Conference; November 7-11, 2011; San Francisco, CA.

EVEREST II

• Not high risk patients! All surgical candidates!

• Only 27% with FMR

• No data comparing MitraClip vs surgery vs conservativetreatment in high surgical risk patients

Control group

Standard of care

N~278

Clinical and TTE follow-up: Baseline, Treatment, 1-week (phone),

1, 6, 12, 18, 24, 36, 48, 60 months

MitraClipN~278

~555 patients enrolled at up to 85 US sites

Randomize 1:1

Symptomatic heart failure subjects who are treated per standard of care

Determined by the site’s local heart team as not appropriate for mitral valve surgery

Specific valve anatomic criteria

Significant FMR (≥3+ by core lab)

2013 ACCF/AHA Guideline for the Management of Heart Failure: Circulation 2013; 128:e240-327.

COAPT: Trial design

Survival of transcatheter mitral valve repair compared to surgical and conservative

treatment in high risk patients

MJ Swaans, ALM Bakker, A Alipour, MC Post, JC Kelder, TL de Kroon, FD Eefting, BJWM Rensing,

JAS Van der Heyden

JACC Cardiovasc Interv. 2014 Aug;7(8):875-81.

St Antonius Hospital, Nieuwegein, The Netherlands

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MitraClip intervention improves survival

Kaplan-Meier Survival Curves

MitraClip therapy is superior

to conservative treatment and

survival rates are comparable

to surgery in high-surgical-risk

patients with symptomatic MR

(DMR and FMR)

Swaans et al. JACC Cardiovasc interventions 2014

MitraClip intervention improves survival

Kaplan-Meier Survival Curves

Velazquez et al. JACC Cardiovasc interventions 2014

• 351 MitraClip patients vs propensity matched patients on OMT

• OMT patients from the DUKE Echo Laboratory Database (85.000)

• 239 optimally matched patients with identical baseline characteristics

• 1 year mortality rates were 22.4% for MitraClip vs 32.0% for OMT

MitraClip intervention improves survival

Giannini te al. Am J Cardiol. 2016

• 70 Mitraclip patients compared to 90 OMT patients, only FMR

• 60 optimally matched patients

• Overall survivalrates after 1 year: 89.7% vs 64.3%

• 3 year survival was 61.4% vs 34.9%

• Significantly lower rehospitalization rates

MitraClip in Elderly

• 1,064 patients stratified by age

• 525 patients ≥76 years and 539 patients <76 years

• higher logistic EuroSCORE (25% vs.18%, p<0.0001) and more women

(47.2% vs. 29.3%, p<0.0001).

• More likely to have a preserved ejection fraction and degenerative MR

• Age was the most frequent reason for non-surgical treatment in the elderly

(69% vs. 36%, p<0.0001).

• The intrahospital MACCE (death, myocardial infarction, stroke) was low in

both groups (3.5% vs. 3.4%, p=0.93)

• Proportion of non-severe mitral regurgitation at discharge was similar (95.8% vs.

96.4%, p=0.73).

• A logistic regression model did not reveal any significant impact of age on acute

efficacy and safety of MitraClip therapy.

Schillinger et al. Eurointervention 2013

• 828 patients

• Stratified by the number of non-cardiac comorbidities

• The 375 (45%) patients with multiple (≥2) non-cardiac comorbidities presented with higher NYHA classes, higher logistic

Euroscores, higher levels of NT-proBNP and a shorter 6-min walk

distance.

• Rates of intrahospital death and intrahospital MACCE were similar

• 30-day MACCE rate was significantly higher (6.4 vs. 3.6%).

• However, both patient groups showed a similar clinical

improvement after 30 days.

• Renal insufficiency was the only non-cardiac comorbidity which was independently associated with the 30-day MACCE rate.

Zuern et al. Clin Res Cardiol 2015

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• 213 MitraClip patients, 45.5% were classified as frail

• Frail patients had a similar device success rate (81% vs. 85%; p = 0.56)

• Similar improvement in 6MWT and NYHA class

• More pronounced improvement in Quality of Life

• Mortality at 6 weeks was significantly higher in frail (8.3%) compared with non-frail (1.7%) patients (p = 0.03)

• Hazards of death and heart failure were significantly increased

Metze et al. JACC Cardiovasc interventions 2017

Conclusions

• Poor prognosis in absence of surgery

• Even with optimal medical therapy

• Surgery in FMR patients is associated with significant morbidity and mortality

• MitraClip is a viable alternative

• We can add “Life to Years”, but might also add “Years to Life”

• Elderly and frail patients can still benefit!

Thank you for your attention!