winthrop institute for heart care managing mitral...

WINTHROPInstitute for Heart Care

Managing Mitral

Regurgitation in HF Patients:

Is it the Chicken or the Egg?

Srihari S. Naidu, MD, FACC, FSCAI, FAHAAssociate Professor of Medicine, SUNY – Stony Brook

Director, Cardiac Catheterization Laboratory,

Winthrop University Hospital, Mineola, NY

Past Trustee, SCAI ; Trustee, Brown University


Classification of MR

Incompetent mitral

valve closure

Systolic retrograde blood flow

from the LV into the LA

Mayo Clinic (www.mayoclinic.com)

Primary

(Degenerative):Anatomic abnormality

of the mitral valve

• Leaflets

• Subvalvular

apparatus

• Chordae and

papillary muscles

Secondary

(Functional):LV dilation; often

secondary to ischemic

heart disease

• Leads to mitral

annular dilation

• Incomplete coaptation

of the mitral valve


Classification of MR

Srihari S. Naidu, MD, MitraClip Program, Winthrop University Hospital

“The Valve” “The Ventricle”

Usually myxomatous Ischemic or not


Chicken (LV) or Egg (MV)? How we’ve thought of things so far …

Primary MR LV Dysfx Mixed MR and

Worsening EF/HF

LV Dysfx Sec MR Worsening EF/HF

Fix the MR prior to LV dysfunction/AF/pHTN to avoid progression

If EF already reduced, probably still worthwhile to fix until EF < 20-25

Improve heart function to minimize MR and progression

-Revascularization

-Bi-V pacemaker/ICD

-Medications for Remodeling

Continued

3-4+ MR ?


MR and LV Dysfunction

Increasing Mitral

Regurgitation

Increase

Load/Stress

Muscle

Damage/Loss

Dysfunction

of Left Ventricle

Dilation of

Left Ventricle1 year

mortality

up to

57%1

1 Cioffi G, et al. Functional mitral regurgitation predicts 1-year mortality in elderly patients with systolic chronic heart failure.

European Journal of Heart Failure 2005 Dec;7(7):1112-7

Both MR and LV Dysfunction

Contribute to Progressive

Heart failure and Secondary

Worsening of Each Other


6

Prevalence of Valve Disease

According to Age

Nkomo et al. Burden of Valvular Heart Diseases: A Population-based Study,

Lancet, 2006; 368: 1005-11.

> 9.3% for ≥75 year olds

14

12

10

8

6

4

2

0

Pre

vale

nce (

%)

of m

odera

te

to s

evere

valv

e d

isease

Aortic valve disease

Age (years)

<45 45-54 55-64 65-74 >75

Mitral valve disease

All valve disease


7

MR and Heart FailurePrevalence in CHF

Moderate or

severe MR

present in

40%

Heart Failure and significant MR are inseparable

Patel JB, et al. J Card Fail 2004;10:285-291; Go AS, et al. Circulation 2013;127:e6.

0

10

20

30

40

50

60

70

%

None

Moderate

Mod-Severe

Severe

Advanced Heart Failure


The Egg: Degenerative

(Primary) MR


9

Asymptomatic Primary MRNatural History

Avierinos JF, et al. Circulation 2002;106:1355

100

90

80

70

60

50

Surv

ival %

0 2 4 6 8 10

2 RF

1 RF

95 ±2

70 ±5

55 ±9

Risk Factors:

Age 50 yrs

Atrial fibrillation

LA enlargement

Flail

Mild MR

MR 3

or

EF <50%

Years after diagnosis


10

Asymptomatic Primary MRSeverity and Survival

Enriquez-Sarano M et al. NEJM 2005;352:875-83

Worse Survival

100

90

80

70

60

50

0

Su

rviv

al (%

)

Years

0 1 2 3 4 5

P<0.01

ERO <20mm2 (91 ±3%)

ERO 40mm2 (58 ±9%)

ERO 20-39mm2

(66 ±6%)

More CV Events

70

60

50

40

30

20

10

0

Ra

te o

f C

ard

iac E

ve

nts

%

Years

0 1 2 3 4 5

P<0.01

ERO <20mm2 (15 ±4%)

ERO 20-39mm2

(40 ±7%)

ERO 40mm2 (62 ±8%)


11

Flail Mitral LeafletNatural History

Ling L, et al. N Engl J Med 1996; 335:1417-1423

100

80

60

40

20

0

Surv

ival %

Years After Diagnosis

0 1 2 3 4 5 6 7 8 9 10

P<0.001

Class I or II

Class III or IV

Mortality4% per year

34% per year


EF and Surgical Outcome

100

80

60

40

20

0

Surv

ival %

Years

0 1 2 3 4 5 6 7 8 9 10

EF 60%

EF 50-60%

EF <50%

P=0.0001

72 ±4%

53 ±9%

EF <60% is Abnormal in MR

32 ±12%

Enriquez-Sarano M, et al., Circulation 1994;90:830-837


13

Symptoms and SurgeryOutcome with Primary MR

100

80

60

40

20

0

Surv

ival %

Years

0 1 2 3 4 5 6 7 8 9 10

NYHA I-II

NYHA III-IV

P<0.0001

90 ±2

76 ±5

73 ±3

48 ±4

Tribouilly CM et al., Circulation 1999;99:400-5


14

Early Surgery Is BetterPatients without Class I Indications

100

80

60

40

20

0

Surv

ival %

Follow-up, y

0 5 10 15 20

Suri R et al., JAMA 2013;310:609-16

Early surgery

Medical management

Log-rank P<.001


Summary for Primary MR

• Prognosis governed by:

– Number of related risk factors

– Severity (ERO or MR grade)

– Ejection Fraction

– NYHA Class

• Outcome governed by:

– Surgical repair/replacement once indicated

– Early consideration


The Chicken: Secondary

(Functional) MR


17

• Papillary muscle

displacement

Trichon BH, et al. Am J Cardiol 2003;91:538-43

Secondary Mitral RegurgitationA Ventricular Problem

Regional or

Global Dysfunction

• Annular flattening

• Leaflet tethering


18

Secondary Mitral RegurgitationA Harbinger of Poor Outcome

Two-fold Increase Risk of DeathGrigioni F, et al. Circulation 2001;103:1759-64;

Basket JF, et al. Can J Cardiol 2007;23:797-800

1.0

0.8

0.6

0.4

0.2

0.0

Su

rviv

al (%

)

Years

0 1 2 3 4 5

P<0.001

50

40

30

20

10

0D

ea

th o

r h

ea

rt fa

ilure

ho

sp

ita

liza

tio

n %

Follow-up time (days)

0 365 730 1095

P=0.0006

MI w/o MR

MI with MR

61 ±6

38 ±5

Mitral

Regurgitation

No Mitral

Regurgitation

Post-MI SOLVD (EF >35%)


19

Hospitalization-free survival decreased with

increased MR severity1

100

80

60

40

20

0

Ho

sp

ita

liza

tio

n-f

ree

Su

rviv

al (%

)

Years

0 1 2 3 4 5 6 7

P<0.01

No MR(40%)

Severe MR

7%)

Mild/mod MR

(25%)

Transplant-free survival decreased with

increased MR severity2

100

90

80

70

60

50

40

Tra

nsp

lant-

fre

e S

urv

iva

l (%

)

Days

0 500 1000 1500 2000

Grade IV

(46.5 ±6.7%)

Grade III

(68.5 ±4.6%)

Secondary Mitral RegurgitationIncreased Severity = Increased Morbidity

1. Rossi A, Dini FL, Faggiano P, et al. Independent prognostic value of functional mitral regurgitation in patients with heart failure: a quantitative analysis of 1256 patients with ischemic and non-ischaemic dilated cardiomyopathy. Heart. 2011;97(20):1675-1680.

2. Bursi F, Barbieri A, Grigioni F, et al. Prognostic implications of functional mitral regurgitation according to the severity of the underlying chronic heart failure: a long-term outcome study. Eur J Heart Fail. 2010;12(4):382-388.

Grade II

(64.4 ±4.9%)

No MR & Grade I

(82.7 ±3.1%)


Surgery for Secondary MR

Wu AH, et al. J Am Coll Cardiol 2005;45:381-87No Mortality Benefit

1.0

0.8

0.6

0.4

0.2

0.0

Event-

fre

e S

urv

ival

Time (Days)

0 500 1000 1500 2000


Summary for Secondary MR

• Prognosis governed by:

– Severity of MR

– Underlying degree of LV dysfunction, NYHA

class, and comorbidities

• Outcome not apparently improved by

surgical repair or replacement


What are our options?

Untreated severe MR (degenerative OR functional) is associated with increased morbidity and mortality

Natural History Summary

For DMR and FMR


23

Timing of SurgeryACC/AHA Guidelines – Primary MR

Consider surgery whenSymptoms

or

LV dysfunction (EF<60%, ESD≥40 mm)

Repair preferred over replacement

Nishimura R, et al., J Am Coll Cardiol 2014;63:2438-88


24

Timing of SurgeryACC/AHA Guidelines – Primary MR

For patients without symptoms:

likelihood of repair success >95%

and

mortality rate <1%

Can be done if



25

Surgical InterventionACC/AHA Guidelines – Secondary MR

Surgery may be considered for severe

symptoms despite optimal GDMT (IIb)

Also while undergoing other CV

surgery, if severe (IIa) or moderate (IIb)



General Principles: The

World Prior to MitraClip

Primary

Surgery for symptoms or

LV dysfunction

Secondary

Asymptomatic pts

if repairable

and low risk

Revascularization and

Medical

therapy first

No medical

option for valve

Consider CRT

Surgery only in highly

selected patients with HF


An Untreated Population

Total MR Patients1,2

Eligible for Treatment3,4

(MR Grade ≥3+)

4,100,000

1,700,000

Annual MV Surgery5

Annual Incidence3

(MR Grade ≥3+)250,000

30,000Only 2% Treated Surgically

14% Newly Diagnosed

Each Year

1,670,000

Untreated Large

and Growing Clinical

Unmet Need

1. US Census Bureau. Statistical Abstract of the US: 2006, Table 12.

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

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

4. ACC/AHA 2008 Guidelines for the Management of Patients with Valvular Heart Disease, Circulation: 2008

5. Gammie, J et al, Trends in Mitral Valve Surgery in the United States: Results from the STS Adult Cardiac Database, Annals of Thoracic Surgery 2010.

Mitral Regurgitation 2009 U.S. Prevalence


Would New Options Change

the Paradigm and Outcome?

Medical Therapy

Less Invasive

Increased MR Reduction

MV SurgeryMitraClip®


MitraClip System


Severe Myopathy and Severe MR:

Is The Clip an Option?

In DMR: Too Late, EF severely reduced,

surgery becomes risky

In FMR: Myopathy continues to progress,

there is an acute LV insult at surgery on an

already diseased heart, and/or complete

elimination of MR increases afterload


279 Patients enrolled at 37 sites

Randomized 2:1

Echocardiography Core Lab and Clinical Follow-Up:

Baseline, 30 days, 6 months, 1 year, 18 months, and

annually through 5 years

Control GroupSurgical Repair or Replacement

N=95

Significant MR (3+-4+)Specific Anatomical Criteria

Device GroupMitraClip System

N=184

EVEREST II Randomized


Primary Endpoints

Safety

• Major Adverse Event Rate at 30 days

• Per protocol cohort

• Superiority hypothesis

Effectiveness

• Clinical Success Rate– Freedom from the combined outcome of

• Death

• MV surgery or re-operation for MV dysfunction

• MR >2+ at 12 months

• Per protocol cohort

• Non-inferiority hypothesis

Pre-Specified MAEs

Death

Major Stroke

Re-operation of Mitral Valve

Urgent / Emergent CV Surgery

Myocardial Infarction

Renal Failure

Deep Wound Infection

Ventilation >48 hrs

New Onset Permanent Atrial Fib

Septicemia

GI Complication Requiring

Surgery

All Transfusions ≥2 units


EVEREST 4 Year Results

Percutaneous

(n = 161)

Surgical

(n = 73)

P Value

Composite

Efficacy

Endpoint

39.8% 53.4% 0.070

Death 17.4% 17.8% 0.914

Surgery or Re-

operation for

Mitral Valve

Dysfunction

24.8% 5.5% < 0.001

MR 3+ or 4+ 21.7% 24.7% 0.745

Roughly 75% were DMR


Age: 82 ±9 years

Prior MI: 24%

Prior stroke: 10%

Diabetes: 30%

COPD: 32%

Renal disease: 28%

Mean STS Risk

13.2%

Lim et al. Improved functional status and quality of life in prohibitive surgical risk

patients with degenerative mitral regurgitation after transcatheter mitral valve repair,

JACC 2014;64:182-192.

Prohibitive Surgical Risk

DMR Cohort (n=127)


Prohibitive Surgical Risk

DMR Cohort (n=127)

Left Ventricular Volumes

Hospitalizations for Heart Failure

Left Ventricular End Diastolic Volume Left Ventricular End Systolic Volume

(N = 69)Paired

Data(N=69)

0.67

0.18

0.0

0.2

0.4

0.6

0.8

1.0

1 Year Prior… 1 Year Post…

HF

Ho

spit

aliz

atio

n R

ate

pe

r P

atie

nt Y

ear

73% Reduction

125

109

60

70

80

90

100

110

120

130

140

Baseline 1 Year

Vo

lum

em

L

-16 mL

0

49

46

30

35

40

45

50

55

60

Baseline 1 Year

0

-3 mL

4+

4+

3+

3+

2+

2+

1+

1+

0%

20%

40%

60%

80%

100%

Baseline 12 Months

Patien

ts (%

)

Mitral Regurgitation Grade

0

1+

3+

4+

2+

I

II

IV

III


The MitraClip Clip Delivery System is indicated for the

percutaneous reduction of significant symptomatic

mitral regurgitation (MR ≥ 3+) due to primary

abnormality of the mitral apparatus [degenerative

MR] in patients who have been determined to be at

prohibitive risk for mitral valve surgery by a heart

team, which includes a cardiac surgeon experienced

in mitral valve surgery and a cardiologist experienced

in mitral valve disease, and in whom existing

comorbidities would not preclude the expected

benefit from reduction of the mitral regurgitation.

MitraClip Indications


Transcatheter Mitral Repair

May be considered for prohibitive risk patients

with primary MR and severe symptoms despite

GDMT (class IIb)

Why not functional MR??

ACC/AHA Guidelines – Primary MR


Interaction of Age and MR Type


41

Randomize 1:1

Clinical and TTE follow-up:

Baseline, Treatment, 1-week (phone)

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

Control group

Standard of care

N=215

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

MitraClip

N=215

Significant FMR (≥3+ by core lab)

Trial DesignGoals: 430 patients at 75 US sites

Clinical Investigational Plan 11-512:

Version 5.1, November 11, 2013. COAPT

protocol approved by FDA July 27, 2012


Summary of MitraClip

MitraClip therapy safely reduces DMR in patients at

prohibitive risk for MV surgery

In this group of prohibitive risk DMR patients, MitraClip

therapy provides meaningful clinical improvements

Reduction of LV volumes

Improvements in NYHA Functional Class

Improvements in Quality of Life

Reduction in Hospitalizations for Heart Failure

Results in FMR may be even better but await COAPT


43

Is it the Chicken or the Egg?

Yes! But it doesn’t matter ….

as significant MR is always

contributory to worse prognosis

Managing MR in HF


Thank You

winthrop institute for heart care managing mitral...

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