Mitral Clip vs Surgery

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Management of Mitral Regurgitation in Heart Failure

Donna Mancini MD

Professor of Medicine

Mount Sinai Icahn School of Medicine

Disclosures

• none

“Epidemic” of Heart Failure in the US

• 5.2 million cases

• 650,000 incidence cases/yr

• 1 million hospital admissions annually

• Rehospitalization rate of 25% within 1 month; 50% within 6 months

• 50% of patients diagnosed with heart failure will die in 5 years

• 300,000 deaths/yr

• Cost >$40 billion/yr

Heart Failure Management

Arnold JMO, Howlett JG, et al. Can J Cardiol 2007;23(1):21-45.

10%

Angiotensin Neprilysin Inhibition With EntrestoDoubles Effect on Cardiovascular Death of Current

Inhibitors of the Renin-Angiotensin System

20%

30%

40%

ACEinhibitor

Angiotensinreceptorblocker

0%

% D

ecre

ase

in M

ort

alit

y

18%

20%

Effect of ARB vs placebo derived from CHARM-Alternative trialEffect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial

Effect of LCZ696 vs ACE inhibitor derived from PARADIGM-HF trial

Angiotensinneprilysininhibition

15%

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Mitral Clip vs Surgery

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VO2 >20 VO2 10-20 VO2 <10

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Mitral Clip vs Surgery

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Background

HF patients who develop MR from LV dilation have reduced quality-of-life, frequent HF hospitalizations and decreased survival

• Guideline-directed medical therapy (GDMT) and cardiac resynchronization therapy (CRT) can reduce MR

• Whether further correcting secondary MR improves the prognosis of pts with HF is unknown

• Surgery with a downsized annuloplasty ring has not been demonstrated to be beneficial for secondary MR, and has a high recurrence rate

• the MitraClip device reduces MR and registries suggested that the Clip is safe and provide symptomatic benefit

Transcatheter Mitral-Valve Repair in Patients with Heart Failure. Gregg W. Stone, M.D., the COAPTInvestigators N Engl J Med Vol 379:2307-2318

Percutaneous Repair or Medical Treatment for Secondary Mitral Regurgitation. Jean-François Obadia, M.D., Ph.D. the MITRA-FRInvestigators N Engl J Med Vol 379:2297-2306

CoAPT-The best of times

The thrill of victory

MITRA-FRThe worst of timesThe agony of defeat

Secondary / Functional

‐Grigioni et al Circulation2001 ‐Baumgartner et al. Europ Heart J 2017

Percutaneous Repair of a Mitral Valve.

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

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Mitral Clip vs Surgery

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CoApt Inclusion Criteria

• Ischemic or non-ischemic CM

• LVEF 20%-50% and LVESD ≤70 mm

• 3+ or 4+ secondary MR confirmed by an echo core lab

• NYHA functional class II-IV despite a stable maximally-tolerated GDMT regimen and CRT (if appropriate)

• Pt has had at least one HF hospitalization within 12 months and/or a BNP ≥300 pg/ml* or a NT-proBNP≥1500 pg/ml*

• Not appropriate for MV surgery by local heart team assessment

• Interventionalist believes secondary MR can be treated by MitraClip

CoAPT Key Exclusion Factors

stage D HF, hemodynamic instability or cardiogenic shock

• Untreated clinically significant CAD requiring revascularization

• COPD on continuous home O2 or chronic oral steroid use

• Severe pulmonary hypertension or moderate or severe right ventricular dysfunction

• Aortic or tricuspid valve disease requiring surgery or transcatheter intervention

• Mitral valve orifice area <4.0 cm2 by site-assessed TTE

• Life expectancy <12 months due to non-cardiac conditions

Central ECHO LAB and Eligibility Committee

• Central Echo Core Lab confirmed 3+ -4+ secondary MR

• Potential pts presented to a Central Eligibility Committee (CEC) consisting of a HF specialist and expert mitral valve surgeon

• The CEC confirmed eligibility criteria were met, especially 1) GDMT, and CRT, defibrillators and revascularization 2) mitral valve surgery would not be offered, even if randomized to control

• Pts not meeting these criteria were rejected, or deferred and could be re-presented after suitable GDMT had been instituted if the ptremained symptomatic and repeat echo still showed 3+-4+ MR

Tier 1 (N=570; 85.7%)

Tier 2 (N=70; 10.5%) Tier 3 (N=25; 3.8%)

EROA ≥ 0.3 cm2

or PV systolic flow reversal

EROA 0.2 cm2 to <0.3 cm2 with one of the following:- RVol ≥ 45 ml/beat- RF ≥ 40%- VC width ≥ 0.5 cm

EROA not measured or <0.2 cm2, with at least 2 of the following:- RVol ≥ 45 ml/beat- RF ≥ 40%- VC width ≥ 0.5 cm- PISA radius > 0.9 cm- Large (≥ 6.0 cm) holosystolic

jet wrapping around LA- Peak E velocity ≥ 150 cm/s

EROA = Effective Regurgitant Orifice Area; LA = Left Atrium; PV = Pulmonary Valve; RVol = Regurgitant Volume; RF = Regurgitant Fraction; VC = Vena Contracta; PISA = Proximal Isovelocity Surface Area

Echo Criteria for enrollment in CoAPT Study Flow and Follow-up1576 pts with HF and MR considered for enrollment

between September 25th, 2012 and June 23th, 2017 at 89 centers in the US and Canada

MitraClip + GDMTN=302

GDMT alone

N=312

Reasons for exclusionInadequate MR or DMR (n=244)Not treated with GDMT (n=79)

All inclusion criteria not met (n=85)Exclusion criteria present (n=34)

Echo criteria not met (n=255)Incomplete screening

or other (n=419)

RandomizedN=614 at 78

sites

IneligibleN=911

Roll-in casesN=51 at 34

sites

Eligible for enrollment

N=665

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Mitral Clip vs Surgery

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Baseline Characteristics (i)MitraClip +

GDMT (N=302)GDMT alone

(N=312)MitraClip + GDMT

(N=302)GDMT alone

(N=312)

Age (years) 71.7 ± 11.8 72.8 ± 10.5 BMI (kg/m2) 27.0 ± 5.8 27.1 ± 5.9

Male 66.6% 61.5% CrCl (ml/min) 50.9 ± 28.5 47.8 ± 25.0

Diabetes 35.1% 39.4% - ≤60 ml/min 71.6% 75.2%

Hypertension 80.5% 80.4% Anemia (WHO) 59.8% 62.7%

Hyperchol. 55.0% 52.2% BNP (pg/mL) 1015 ± 1086 1017 ± 1219

Prior MI 51.7% 51.3% NT-proBNP (pg/mL) 5174 ± 6567 5944 ± 8438

Prior PCI 43.0% 49.0% STS replacement sc 7.8 ± 5.5 8.5 ± 6.2

Prior CABG 40.1% 40.4% - ≥8 41.7% 43.6%

Prior stroke or TIA 18.5% 15.7% Surgical risk (central eligibility committee)

PVD 17.2% 18.3% - High* 68.6% 69.9%

COPD 23.5% 23.1% - Not-high 31.4% 30.1%

H/o atrial fibr 57.3% 53.2% * STS repl score ≥8% or one or more factors present predicting extremely high surgical risk

Baseline Characteristics (ii)HF parameters

MitraClip +GDMT (N=302)

GDMT alone(N=312)

Echo core labMitraClip +

GDMT (N=302)GDMT alone

(N=312)

Etiology of HF MR severity

- Ischemic 60.9% 60.6% - Mod-to-sev (3+) 49.0% 55.3%

- Non-ischemic 39.1% 39.4% - Severe (4+) 51.0% 44.7%

NYHA class EROA, cm2 0.41 ± 0.15 0.40 ± 0.15

- I 0.3% 0% LVESD, cm 5.3 ± 0.9 5.3 ± 0.9

- II 42.7% 35.4% LVEDD, cm 6.2 ± 0.7 6.2 ± 0.8

- III 51.0% 54.0% LVESV, mL 135.5 ± 56.1 134.3 ± 60.3

- IV 6.0% 10.6% LVEDV, mL 194.4 ± 69.2 191.0 ± 72.9

HF hosp w/i 1 year 58.3% 56.1% LVEF, % 31.3 ± 9.1 31.3 ± 9.6

Prior CRT 38.1% 34.9% - 40% 82.2% 82.0%

Prior defibrillator 30.1% 32.4% RVSP, mmHg 44.0 ± 13.4 44.6 ± 14.0

Primary Effectiveness EndpointAll Hospitalizations for HF within 24 months

HR (95% CI] =0.53 [0.40-0.70]

P<0.001

0 3 6 9 12 15 18 21 24

50

100

150

200

250

300

0

MitraClip + GDMT

GDMT alone

160in 92 pts

283in 151 pts

Cu

mul

ativ

eH

F H

osp

italiz

atio

ns

(n)

Time After Randomization (Months)MitraClip

GDMT

302 286 269 253 236 191 178 161 124

312 294 271 245 219 176 145 121 88

No. at Risk:

All-cause MortalityA

ll-ca

use

Mor

talit

y (%

)

0%

20%

40%

60%

80%

100%

Time After Randomization (Months)0 3 6 9 12 15 18 21 24

46.1%

29.1%

HR [95% CI] = 0.62 [0.46-0.82]

P<0.001

MitraClip + GDMTGDMT alone

302 286 269 253 236 191 178 161 124312 294 271 245 219 176 145 121 88

No. at Risk:

MitraClip + GDMT

GDMT alone

NNT (24 mo) =5.9 [95% CI 3.9, 11.7]

Primary Safety EndpointFreedom from Device-related Complications within 12 months

MitraClip procedure attempted N=293

Device-related complications 9 (3.4%)

- Single leaflet device attachment 2 (0.7%)

- Device embolization 1 (0.3%)

- Endocarditis requiring surgery 0 (0.0%)

- Mitral stenosis requiring surgery 0 (0.0%)

- Left ventricular assist device implant

3 (1.2%)

- Heart transplant 2 (0.8%)

- Any device-related complication requiring non-elective CV surgery

1 (0.3%)

*KM estimate; **Calculated from Z test with Greenwood’s method of estimated variance against a pre-specified objective performance goal of 88%

50%

60%

70%

80%

90%

100% 96.6%*

88% OPC

94.8% [95% LCL]

P<0.001

Conclusions

• Among HF patients w moderate-to-severe fnMR who remained symptomatic despite GDMT, Mitral Clip lowered the rate of HF hosp and all-cause mortality in 24 months vs medical therapy alone.

• The rate of freedom from device-related complications exceeded a prespecified safety threshold.

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Mitral Clip vs Surgery

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MitraClip Crossovers in GDMT-Assigned Patients(N=312)

• MitraClip crossover before 24 months (N=5)*

• Not eligible for crossover at 24 months (N=169)

– Death: 124

– LVAD: 16; Transplant: 9

– Withdrawals: 26 ; Lost to follow up: 3 ;Other: 2

• MitraClip crossover eligible at 24 months (N=138)

• MitraClip crossover between 24-36 mos(N=53/138; 38.4%)

• Total Crossover (N=58/312; 18.6%)

• Time to crossover: Median: 25.5 months; Range0.2-33 mo

• Follow-up after crossover: Median: 7.7 months; Range: 0-44 mo

Percutaneous Repair or Medical Treatment for Secondary Mitral Regurgitation.Obadia JF, for the MITRA-FR Investigators N Engl J Med Vol 379:2297-2306

MITRA-FR Study Design

Objective to evaluate the clinical efficacy of mitral clip in 

addition to medical Rx in HF patients and severe  functional

MR vs medical treatment alone.

A total of 304 patients with severe secondary mitral regurgitation were randomly assigned to undergo percutaneous valve repair or to receive medical therapy

Primary Endpoint “Composite” All‐Cause Deaths or Unplanned  rehospitalization for Heart failure at 12 months

MITRA-FRInclusion Criteria

• Symptomatic despite Optimal Treatment (NYHA ≥II).

• At least one hospitalization for HF within 12 months preceding randomization

• Severe Secondary MR ERO > 20 mm² or reguritantvolume >30 mL/beat

• 15% < EF < 40%

• Not eligible for surgery “Heart Team”

• Centralized echocardiographic Corelab

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452 Patients

307 Randomized

152 Patients 152 Patients

145 not eligible

3 consent Issues

109 Patients 137 Patients

Intention To Treat

Per‐protocolAnalysis

15 Exclusions43 Exclusions

Mitraclip Control

Follow‐up > 99%

Obadia J-F et al. N Engl J Med 2018;379:2297-2306

Baseline characteristics

NYHA  Class III n ‐ (%) 82 (53.9) 96 (63.2%) 0.27

NYHA  Class IV n ‐ (%) 14 (9.2) 12 (7.9%)

CharacteristicsPercutaneousRepair  

Group (n=152)

Optimal Medical  TreatmentGroup  

(n=152)P value

Age year mean (±SD) 70.1 ± 10.1 70.6 ± 9.9 0.69

>75 year n (%) 51 (33.6) 59 (38.8%) 0.40

Males n ‐ (%) 120 (78.9) 107 (70.4%) 0.11

Ischemic Cardiomyopathy n ‐ (%) 95 (62.5) 60% 85 (56.3%) 0.29

NYHA  Class II n ‐ (%) 56 (36.8) 44 (28.9%)

LVEF mean (±SD) 33.3 ± 6.5 EF=33% 32.9 ± 6.7 0.79

Effect regurg. Orif. area ‐ mm2 mean (±SD) 31 ± 10 S=31mm2 31 ± 11 0.42

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Mitral Clip vs Surgery

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MITRA FR RESULTS

• Death or hospitalization for heart failure (HF): 54.6% of the percutaneous mitral valve repair group vs. 51.3% of the medical therapy group (p = 0.53)

• Death: 24.3% of the percutaneous mitral valve repair group vs. 22.4% of the medical therapy group (p = NS)

• Hospitalization for HF: 48.7% of the percutaneous mitral valve repair group vs. 47.4% of the medical therapy group (p = NS)

0

10

20

30

40

50

60

Clip GDMT

Death or HF Hospitalization

P=0.53

Survival without a Primary Outcome Event-Death and HF Hosp

Obadia J-F et al. N Engl J Med 2018;379:2297-2306

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* Safety Peri procedural complications

Urgent conversion to heart surgery 0

Peri‐procedural Mortality (at 3 days) 0

Vascular complication requiring surgery/ Hemorrhage transfusion 5 (3.5%)

Cardiac embolism (Gas embolism / Stroke) 2 (1.4%)

Tamponade 2 (1.4%)

* Efficacy Technical Implantation Success MVARC 138 ( 96% )‐ 1 Clip 46%‐ 2 Clips  45%‐ 3+ Clips9%

Prespecified Secondary Endpoints

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Secondary Echocardiographic End Points at 12months

Percutaneous Repair Group  (n=152)

Optimal Medical Treatment  Group (n=152)

P value for  comparison  between  study  groups

Change from baseline in  echocardiographic  measures

N Value

P valuebetweenBaselineand 12Mo

N Value

P value  between  

Baseline and  12 Mo

Effective regurgitant orifice  area ‐ mm² 60

‐15[‐23.5 ; ‐8] <0.0001 71 ‐4 [‐11 ; 5] 0.03 <0.0001

End‐systolic diameter ‐ mm 89 2 [‐2 ; 7] 0.002 81 0 [‐3 ; 4] 0.92 0.06

Ejection fraction ‐ % 86 ‐3 [‐8 ; 4] 0.14 76 2 [‐4 ; 8] 0.02 0.004

Pulmonary artery systolicpressure ‐ mmHg 64

‐6.5[‐18 ; 4.5] 0.001 59 ‐3 [‐17 ; 3] 0.007 0.81

6‐minute walk variation ‐ m 73 25 [‐40 ; 71] 0.08 57 19 [‐27 ; 75] 0.06 0.82

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N = 89 (P<0.001)

MR grade evolution in both groups (paired data)

Less MR in Clip Cohort at 1 yr

N = 77 (P<0.001)

100%

75%

50%

25%

0%

100%

75%

50%

25%

0%

Baseline Discharge 12months Baseline 12months

P< 0.001 15

N = 114 P<0.001 N=114

100%

75%

50%

25%

0%

100%

75%

50%

25%

0%

Baseline 12months Baseline 12months

N = 112 P<0.001 N=112

P = NS

NYHA evolution (paired data)

Prespecified Secondary Endpoints

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Conclusions

• Among patients with severe secondary MR, the rate of death or unplanned hospitalization for heart failure at 1 year did not differ significantly between patients who underwent percutaneous mitral-valve repair in addition to receiving medical therapy and those who received medical therapy alone.

Similarities CoAPt vs Mitra

• Both randomized patients with functional MR to medical therapy versus use of mitral clip

• Both multicenter studies

• Both Prospective

• Both open Label

• Both randomized 1:1

• Both with patients with heart failure and grade 3-4 functional MR

Differences between CoAPT and Mitra

• Similar but distinct differences in patient populations

• Differences in medical management (central committee CoApt)

• Difference in Echo Entry Criteria (more mitral regurgwith smaller ventricles –Co-Apt)

• Differences in primary endpoints

• Differences in sample size and duration of follow-up

CoApt Mitra FR

Endpoint HF hosp at 24 moSafety

Death or HF hosp at 12 mo

Sample Size 614 304

Duration 2 yrs 1 yr

ECHO Enrollment Parameters

EROA>0.3 cm2; LVEF 20-50% LVESV <70

EROA >0.2 cm2

RVol >30 ml/beatLVEF 15-40%

Medical Management

Central Eligibility Committee

Local Site

Investigator Implant experience

100 cardiac surgeriesTrans septal technique3 roll in procedures

Percutaneous Interventions5 Mitra Clips

COAPT (N=614) MITRA-FR (N=304)

EROA, cm2 0.41±0.15 0.31±0.10

<30 cm2 80/591 (14%) 157/301 (52%)

30-40 cm2 270/591 (46%) 95/301 (32%)

>40 cm2 241/591 (41%) 49/301 (16%)

LVEF, % 31±9 33±7

LVEDV, mL/m2 101±34 135±35

Differences in mitral regurgitation severity,left ventricular function and dimensionin the COAPT and MITRA-FR trials

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Mitral Clip vs Surgery

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MR

LV

LA

MR

LV

LA

Severe andProportionate MR

Severe andDisproportionate MR

P3 P3P1P1

A2A2

MR

Proportionate Vs. Disproportionate Secondary MR

LVEDVI >96 ml/m2 (N=56; 10.2%) LVEDVI ≤96 ml/m2 (N=51; 9.3%)

COAPT Trial: Impact of EROA and LVEDV if EROA ≤30 mm2

European Heart Journal - Cardiovascular Imaging, Volume 20, Issue 6, June 2019, Pages 620–624,

CoAPT

MITRA‐FR COAPT RESHAPE HF2

Study designProspective, randomized

Prospective, randomized

Prospective, randomized

Randomization 1:1 in: MC vs GDMT MC vs GDMTMC vs GDMT

Total no. of patients 304 614 420

Enrolment period, year 3.2 4.8

No. of sites 22 85

No. of patients/site/year 2.6 1.6

Inclusion/exclusion criteriaBy European Guidelines6

By American Guidelines8,12

By EACVI recommendations12

≥ 3+)MREROA >20 mm2 and/or RV >30 mL

EROA ≥30 mm2 and/or RV >45 mL

EROA >30 mm2 and/or RV >45 mL

LV ESD, mm ≤70 mm

LV ejection fraction, % ≥15 and ≤40 ≥20 and ≤50≥15 and ≤35 if NYHA II≥15 and ≤45 if NYHA III or IV

GDMT at baseline

GDMT variable adjustment in each group per ‘real‐world’ practice

Stable maximal doses of GDMT, PTCA  and CRT

Stable optimal GDMT PTCA or CRT

Swedish ends 2021

CoApt: 2 yr mortality remains close to 30% in Mitral Clip Arm. These patients remain extremely ill and close to advanced therapies .

Just another step in the HF journey

But in the meantime how should one approach the management ofHF patients with moderate to severe functional MR is a team approach:1. HF MD: Maximize Goal Directed Medical Therapy & Repeat ECHO 2. Echocardiographer : if moderate to severe Mr persists then review ECHO criteria to determine if there is disproportionate MR3. Surgeon and Interventionalist: If disproportionate MR present then Surgery vs Clip

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