Federico M. Asch, MD - Cardiolintranet.cardiol.br/coberturaonline/slides/... · Background (i) •Secondary or functional mitral regurgitation (SMR) is present in >50% of patients

Heart Failure and Secondary Mitral Regurgitation:

Echocardiographic Outcomes

from the COAPT trial

Federico M. Asch, MD

Director, Echocardiographic Core Lab

MedStar Health Research Institute

On behalf of Gregg W. Stone, Michael Mack, Neil J Weissman and the

COAPT Investigators

COAPT (NCT01626079)

Federico M Asch, MD

No personal COI

Institutional conflict

MedStar Health has Institutional contracts for my work as

Director of an Academic Core Lab:

Abbott, Boston Scientific, Edwards, Medtronic, Neovasc,

Livanova, GDS, Mitralign.

Disclosure Statement

COAPT (NCT01626079) is funded by Abbott

Background (i)

• Secondary or functional mitral regurgitation (SMR) is

present in >50% of patients with heart failure (HF), and is

severe in ~10-15%.

• Prognosis is poor when SMR is severe.

• COAPT: Randomized, open-label, multicenter trial in

patients with HF and moderate-to-severe (3+) or severe

(4+) SMR who remained symptomatic despite maximally-

tolerated GDMT.

Death or HF Hospitalization

MitraClip + GDMT

GDMT alone

All-

ca

use

Mo

rta

lity o

r

HF

Ho

sp

ita

liza

tio

n (

%)

0%

20%

40%

60%

80%

100%

Time After Randomization (Months)

0 3 6 9 12 15 18 21 24

67.9%

45.7%

MitraClip + GDMT

GDMT alone

302 264 238 215 194 154 145 126 97

312 244 205 174 153 117 90 75 55

No. at Risk:

HR [95% CI] =

0.57 [0.45-0.71]

P<0.001

NNT (24 mo) =

4.5 [95% CI 3.3, 7.2]

Stone GW et al. NEJM 2018;379:2307-18

Background (ii)

• SMR is a consequence of leaflet tethering and incomplete

leaflet coaptation.

• Evaluation of SMR is challenging, due to asymmetric

leaflet anatomy and regurgitant orifice, eccentric jets and

enlarged left cardiac chambers.

• Expert panels have disagreed on how to define the

severity of SMR, resulting in conflicting European and

American guidelines.

ObjectivesCOAPT Echo Sub-study

1. To describe the echocardiographic MR grading criteria

utilized in COAPT for screening and post-MitraClip

2. To describe the echocardiographic characteristics of the

COAPT population

3. To evaluate the serial echocardiographic outcomes

4. To identify baseline echocardiographic predictors of

clinical outcomes (responders and non-responders to

MitraClip)

Methods

• 614 patients with HF and moderate to severe (3+) or

severe (4+) secondary MR

• Randomized 1:1 to maximally-tolerated GDMT + MitraClip

or GDMT alone.

• Transthoracic echocardiograms (TTE) at baseline, 1, 6,

12, 18, 24 months (to continue to year 5)

• All echo analysis by an independent echo core lab,

adapted from American guidelines (ASE, ACC)

Key Echo Inclusion Criteria

1. LVEF 20% - 50% and LVESD ≤70 mm (ischemic or non-

ischemic)

2. SMR amenable for MitraClip treatment

3. Moderate-to-severe (3+) or severe (4+) SMR confirmed

by an independent echo core laboratory prior to

enrollment

Inclusion Flowchart (i)

Patients with HF and MR evaluated for enrollment in COAPT

N=1,576

Secondary MR,

Severity 3+ or 4+

(graded by 1 of 3 criteria)

Roll-in

subjects

N=51

Randomized

subjects

N=614

Subjects with screening TTEs and

meeting all eligibility requirements

for enrollment in COAPT

N=665

Ineligible N=911Inadequate MR or DMR (n=244)

Echo criteria not met (n=255)

Not treated with GDMT (n=79)

All inclusion criteria not met (n=85)

Exclusion criteria present (n=34)

Incomplete screening/other (n=419)

Inclusion Flowchart (ii)

Secondary MR, Severity 3+ or 4+

(graded by 1 of 3 criteria)

EROA ≥ 0.3 cm2

or

PV systolic flow reversal

N=570 (85.7%)

Tier 1

EROA not measured or <0.2 cm2

With at least 2 of the following:

• RV ≥ 45 ml/beat

• RF ≥ 40%

• VC width ≥ 0.5 cm

• PISA radius > 0.9 cm,

but CW of MR jet not done

• Large (≥ 6.0 cm)

holosystolic jet wrapping

around LA

• Peak E velocity ≥ 150 cm/s

N=25 (3.8%)

Tier 3

EROA 0.2 cm2 - <0.3 cm2

With any 1 of the following:

• RV ≥ 45 ml/beat

• RF ≥ 40%

• VC width ≥ 0.5 cm

N=70 (10.5%)

Tier 2

Baseline Echo Characteristics (i)

Device Group

(N=302)

Control Group

(N=312) P-value

LVEF, % 31.3 ± 9.1 (281) 31.3 ± 9.6 (295) 0.96

LVEDV, ml 194.4 ± 69.2 (281) 191.4 ± 73.0 (295) 0.61

LVESV, ml 135.5 ± 56.1 (281) 134.6 ± 60.4 (295) 0.85

Stroke volume, ml 50.5 ± 16.5 (283) 50.7 ± 16.9 (292) 0.85

LA volume, ml 91.7 ± 36.3 (292) 91.0 ± 44.8 (303) 0.84

RVSP, mmHg 44.0 ± 13.4 (253) 44.6 ± 14.0 (275) 0.60

TR severity 0.16

- Mild (1+) 82.6% (247/299) 80.7% (242/300)

- Moderate (2+) 14.0% (42/299) 16.7% (50/300)

Device Group

(N=302)

Control Group

(N=312) P-value

MR severity, n (%) 0.13

- Moderate to severe (3+) 49.0% (148/302) 55.1% (172/312)

- Severe (4+) 51.0% (154/302) 44.9% (140/312)

PISA radius, cm 0.89 ± 0.17 (293) 0.88 ± 0.18 (308) 0.62

EROA, PISA cm2 0.41 ± 0.15 (289) 0.40 ± 0.15 (303) 0.41

Reg. volume, PISA ml 59.7 ± 21.0 (288) 59.9 ± 23.5 (302) 0.91

Vena contracta, cm 0.58 ± 0.12 (277) 0.58 ± 0.12 (293) 0.88

Peak E, cm/sec 110.6 ± 28.7 (280) 109.4 ± 24.9 (286) 0.60

Baseline Echo Characteristics (ii)

Device Group

(N=302)

Control Group

(N=312) P-value

Pulmonary Vein Flow 0.02

- None (0) 0.0% (0/240) 0.0% (0/234)

- Mild (1+) 0.4% (1/240) 0.9% (2/234)

- Moderate (2+) 12.9% (31/240) 12.4% (29/234)


- Severe (4+) 56.7% (136/240) 44.0% (103/234)

MR Color Flow Jet 0.18

- None (0) 0.0% (0/302) 0.0% (0/312)

- Mild (1+) 0.0% (0/302) 0.0% (0/312)

- Moderate (2+) 6.0% (18/302) 6.7% (21/312)


- Severe (4+) 51.0% (154/302) 45.5% (142/312)

Baseline Echo Characteristics (iii)

Change in LV Volumes Over Time

Ad

juste

d C

ha

ng

e in

LV

ED

V (

mL

) fr

om

Ba

se

line

-25

0

25

50

75

y (Device)

y (Control)

1 6 12 18 24

Months Post Procedure

Device

Control

*p<0.05 (ANCOVA)

*

*

*

*

*

*

Left Ventricular End Diastolic Volume (LVEDV)Paired measures, follow-up minus baseline

Mean ± SE

Subjects with HF death prior to a follow-up visit were assigned the worst observed change from baseline at that visit.

For all other subjects who had missing echo values, multiple imputation was used.

Change in LV Volumes Over Time

Ad

juste

d C

ha

ng

e in

LV

ES

V (

mL

) fr

om

Ba

se

line

Device

Control

-25

0

25

50

75

100

125

y (Device)

y (Control)

Left Ventricular End Systolic Volume (LVESV)Paired measures, follow-up minus baseline

Mean ± SE

Device

Control

*

*

*

*

*

*

**

1 6 12 18 24

Months Post Procedure*p<0.05 (ANCOVA)



Change in Ejection Fraction Over Time

-15

-10

-5

0

5

y (Device)

y (Control)

Ad

juste

d C

ha

ng

e in

LV

EF

(%

) fr

om

Ba

se

line

Left Ventricular Ejection Fraction (LVEF)Paired measures, follow-up minus baseline

Mean ± SE

Device

Control

*

**

*

**

*

**



1 6 12 18 24

Months Post Procedure*p<0.05 (ANCOVA)

Overall MR Severity

72.9%

8.2%

66.7%

9.2%

69.0%

11.4%

75.2%

12.3%

77.2%

15.8%

19.8%

26.1%

27.1%

28.9%

25.7%

35.4%

19.9%

28.1%

21.9%

27.6%

49.0%55.3%

5.9%

37.4%

4.6%

42.2%

4.3%

34.3%

4.3%

41.2%40.8%

51.0%44.7%

1.5%

28.4%

1.7%

19.7%

0.1%

18.9%

0.7%

18.4% 15.8%

0%

20%

40%

60%

80%

100%

≤1+

2+

3+

4+

0.9%

Perc

enta

ge o

f P

atients

Device

0.0%

Control

0.0%

N=302

D=0

N=311

D=0

N=273

D=10

N=257

D=10

N=240

D=32

N=218

D=40

Device

92.7%

Control

34.2%

Device

93.8%

Control

38.1%

Device

94.8%

Control

46.9%

Device

95.0%

Control

40.4%

Device

99.1%

Control

43.4% MR ≤2+

Baseline 30 Days 6 Months 12 Months 18 Months 24 Months

N=210

D=59

N=175

D=75

N=141

D=69

N=114

D=99

N=114

D=78

N=76

D=115

N denotes number of subjects with MR severity data available;

D denotes subject deaths which occurred by the upper end of the visit window, whether or not the TTE was performed

All P<0.001

MR Changes From Baseline to 12 MonthsDevice Group

(N=302)

Control Group

(N=312) P-value

MR Severity, n (%) <0.0001

- Improved by ≥2 grades 84.1% (243/289) 15.9% (44/277)

- Improved by 1 grade 11.1% (32/289) 40.4% (112/277)

- No change 4.8% (14/289) 36.8% (102/277)

- Worsened by 1 grade 0.0% (0/289) 6.9% (19/277)

Pulmonary vein flow, n (%) <0.0001

- Improved 83.6% (107/128) 39.6% (53/134)

- No change 14.8% (19/128) 40.3% (54/134)

- Worsened 1.6% (2/128) 20.1% (27/134)

Vena contracta, cm -0.14 ± 0.17 (110) -0.03 ± 0.16 (186) <0.0001

MR color flow jet <0.0001

- Improved 94.1% (272/289) 54.9% (152/277)

- No change 4.8% (14/289) 34.3% (95/277)

- Worsened 1.0% (3/289) 10.8% (30/277)

Changes From Baseline to 12 Months

Device Group

(N=302)

Control Group

(N=312) P-value

TR severity, n (%) 0.34

- Improved 10.6% (30/282) 13.4% (35/261)

- No change 71.6% (202/282) 70.5% (184/261)

- Worsened 17.7% (50/282) 16.1% (42/261)

RVSP, mmHg -3.5 ± 14.3 (202) -2.1 ± 14.7 (211) 0.13

24-Month All-cause Mortality

or First HF Hospitalization (i)

0.2 0.5 1 1.5 2.5

Favors MitraClip + GDMT Favors GDMT alone

Subgroup MitraClip + GDMT GDMT Alone HR [95% CI] HR [95% CI] P [Int]

All patients 45.4% (128) 67.4% (189) 0.57 [0.45, 0.71]

Baseline LVEF

≥ 30% (median: n=301) 44.1% (62) 60.5% (84) 0.61 [0.44, 0.85]0.29

< 30% (median: n=274) 45.8% (55) 77.6% (98) 0.46 [0.33, 0.64]

> 40% (n=103) 49.7% (22) 53.5% (26) 0.70 [0.39, 1.23]0.26

≤ 40% (n=472) 43.8% (95) 71.8% (156) 0.50 [0.39, 0.65]

LVEDV (median)

≥ 181 mL (n=288) 48.3% (63) 68.0% (92) 0.57 [0.41, 0.79]0.52

< 181 mL (n=287) 41.5% (54) 68.5% (90) 0.49 [0.35, 0.69]

LVESV (median)

≥ 124 mL (n=288) 46.8% (60) 71.1% (97) 0.51 [0.37, 0.71]0.83

< 124 mL (n=287) 43.1% (57) 65.7% (85) 0.55 [0.39, 0.77]

LV Stroke Volume (median)

≥ 49 mL (n=286) 46.0% (60) 65.0% (88) 0.64 [0.46, 0.89]0.30

< 49 mL (n=289) 44.3% (59) 69.5% (89) 0.49 [0.35, 0.69]

LVEDD (median)

≥ 6.1 cm (n=340) 48.4% (76) 71.2% (110) 0.56 [0.41, 0.75]0.94

< 6.1 cm (n=268) 41.9% (52) 64.3% (79) 0.56 [0.39, 0.79]

0.2 0.5 1 1.5 2.5

Subgroup MitraClip + GDMT GDMT Alone HR [95% CI] HR [95% CI] P [Int]

All patients 45.4% (128) 67.4% (189) 0.57 [0.45, 0.71]

MR Severity

3+ (n=320) 36.9% (50) 64.4% (98) 0.48 [0.34, 0.68]0.30

4+ (n=293) 53.4% (78) 71.4% (91) 0.62 [0.45, 0.83]

PISA Radius (median)

≥ 0.87 cm (n=306) 48.2% (72) 66.5% (92) 0.57 [0.42, 0.78]0.86

< 0.87 cm (n=294) 42.0% (52) 67.1% (94) 0.54 [0.39, 0.76]

EROA, PISA (median)

≥ 0.37 cm2 (n=309) 49.8% (75) 73.7% (102) 0.52 [0.38, 0.70]0.91

< 0.37 cm2 (n=282) 37.9% (45) 60.4% (81) 0.54 [0.37, 0.78]

Reg Vol, PISA (median)

≥ 23 mL (n=138) 45.1% (30) 62.2% (38) 0.50 [0.31, 0.81]0.71

< 23 mL (n=122) 40.1% (19) 73.5% (47) 0.43 [0.25, 0.74]

Reg Fraction (median)

≥ 36% (n=135) 45.7% (28) 70.5% (43) 0.44 [0.27, 0.71]0.75

< 36% (n=124) 40.9% (21 67.1% (42) 0.50 [0.29, 0.85]



or First HF Hospitalization (ii)

0.2 0.5 1 1.5 2.5



or First HF Hospitalization (iii)Subgroup MitraClip + GDMT GDMT Alone HR [95% CI] HR [95% CI] P [Int]

Vena Contracta (median)

≥ 0.57 cm (n=294) 46.8% (65) 69.3% (93) 0.53 [0.38, 0.73]0.62

< 0.57 cm (n=275) 44.4% (54) 66.4% (86) 0.59 [0.42, 0.83]

Pulmonary Vein Flow

0 / 1+ / 2+ (n=63) 34.8% (10) 62.7% (19) 0.41 [0.19, 0.89]

0.283+ (n=172) 42.1% (28) 72.5% (64) 0.43 [0.28, 0.68]

4+ (n=238) 49.5% (63) 66.5% (61) 0.65 [0.46, 0.92]

TR severity

≤ 1+ (n=501) 44.7% (107) 64.5% (143) 0.61 [0.47, 0.78]0.21

≥ 2+ (n=98) 49.9% (20) 81.0% (40) 0.43 [0.25, 0.74]

Peak E (median)

≥ 109 cm/sec (n=292) 49.7% (68) 73.7% (98) 0.52 [0.38, 0.72]0.25

< 109 cm/sec (n=274) 41.8% (52) 58.5% (73) 0.69 [0.48, 0.99]

RVSP (median)

≥ 43 mmHg (n=276) 55.8% (69) 76.8% (103) 0.62 [0.45, 0.84]0.79

< 43 mmHg (n=252) 36.1% (40) 53.9% (61) 0.58 [0.39, 0.86]

Tier of Echo Eligibility

Tier 1 (n=530) 47.2% (117) 67.0% (161) 0.58 [0.46, 0.74]

0.21Tier 2 (n=61) 17.4% (4) 67.9% (23) 0.23 [0.08, 0.68]

Tier 3 (n=23) 50.0% (7) 70.0% (5) 0.80 [0.25, 2.54]

Predictors of 24-Month Mortality or First HF Hospitalization

Multivariable Cox regression

Hazard Ratio [95% CI]

P-Value

RVSP (mmHg) 1.02 [1.01, 1.04] 0.005

STS Repl Score 1.12 [1.02, 1.23] 0.020

LVEDV (mL) 1.00 [1.00, 1.01] 0.07

Sex (Female vs Male) 0.64 [0.37, 1.08] 0.09

EROA, PISA (cm2) 2.56 [0.79, 8.26] 0.12

Isch vs Non-Isch CM 0.70 [0.43, 1.13] 0.15

STS Repair Score 0.95 [0.88, 1.04] 0.26

LVEF (%) 1.01 [0.98, 1.03] 0.56

Age (years) 1.01 [0.98, 1.03] 0.57

TR Grade (≥2+ vs ≤1+) 0.90 [0.51, 1.61] 0.73

Hazard Ratio

[95% CI]P-Value

TR Grade (≥ 2+ vs ≤ 1+) 1.60 [1.07, 2.39] 0.022

LVEF (%) 0.98 [0.96, 1.00] 0.027

RVSP (mmHg) 1.01 [1.00, 1.02] 0.032

EROA, PISA (cm2) 3.15 [1.08, 9.21] 0.036

STS Repl Score 1.07 [0.98, 1.18] 0.14

Age (years) 0.99 [0.97, 1.01] 0.24

STS Repair Score 0.96 [0.87, 1.07] 0.47

Isch vs Non-Isch CM 0.92 [0.62, 1.36] 0.66

LVEDV (mL) 1.00 [1.00, 1.00] 0.84

Sex (Female vs Male) 0.97 [0.64, 1.46] 0.87

GDMT AloneMitraClip + GDMT

Limitations

• Echo analysis was blinded to clinical condition, but not to

intervention.

• PISA and hemodynamics after MitraClip have major

limitations. Color Doppler, PV flow and vena contracta are

the most available and reliable methods.

• Subgroup predictive analysis was only done based on pre-

specified plans.

• To overcome survivorship bias, worst case scenario and

multiple imputation methods were used to account for missing

follow-up data (pre-specified).

Conclusions (i)COAPT Echo Sub-study

• To duplicate the COAPT results, specific COAPT

screening echo criteria and expert echo analysis should

be applied to identify proper candidates for MitraClip.

• In patients with HF and 3+ or 4+ secondary MR, TMVr

with MitraClip provided substantial death and HFH

benefits in all echocardiographic subgroups, regardless

of degree of LV dysfunction, LV dimensions, pulmonary

hypertension, severity of TR or individual MR

parameters (all responders).

Conclusions (ii)COAPT Echo Sub-study

• Baseline LVEF, TR and MR severity predicted poor

outcomes in patients with HF treated with GDMT alone,

but not after MR was corrected by MitraClip.

• RVSP was the only independent echocardiographic

predictor of poor outcomes after MitraClip and GDMT

treatments.

Acknowledgments

• COAPT Principal Investigators and Co-authors Gregg W. Stone, Michael J. Mack, William T. Abraham,

JoAnn Lindenfeld, Paul A. Grayburn, Robert J. Siegel, Saibal Kar,

D. Scott Lim, Jonathan G. Zaroff, Jacob M. Mishell, Brian Whisenant

and Neil J. Weissman

• Abbott Structural Heart Global Clinical Affairs Jeffrey Ellis, Kartik Sundareswaran

• Abbott Global Biometrics Yu Shu, Juanjuan Li, Deepika Morishetti, Hong Nie

• All COAPT Sites, Research Coordinators, Heart Teams and Patients

• MedStar Echo Core lab Staff Vladimir Masati, Valiere Morgan, Ma Therese Tupas-Habib, et al.

Documents

Federico M. Asch, MD - Cardiolintranet.cardiol.br/coberturaonline/slides/... · Background (i) •Secondary or functional mitral regurgitation (SMR) is present in >50% of patients