Federico M. Asch, MD Director, Echocardiographic Core Lab MedStar - - PowerPoint PPT Presentation

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-cause Mortality or HF Hospitalization (%)

0% 20% 40% 60% 80% 100%

Time After Randomization (Months)

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.

Objectives

COAPT 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
• r 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=911

Inadequate 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

• r

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)

• Moderate to severe (3+)

30.0% (72/240) 42.7% (100/234)

• 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)

• Moderate to severe (3+)

43.0% (130/302) 47.8% (149/312)

• Severe (4+)

51.0% (154/302) 45.5% (142/312)

Baseline Echo Characteristics (iii)

Change in LV Volumes Over Time

Adjusted Change in LVEDV (mL) from Baseline

• 25

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

Adjusted Change in LVESV (mL) from Baseline

Device Control

• 25

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)

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 Ejection Fraction Over Time

• 15
• 10
• 5

5

y (Device) y (Control)

Adjusted Change in LVEF (%) from Baseline

Left Ventricular Ejection Fraction (LVEF)

Paired measures, follow-up minus baseline Mean ± SE Device Control * * * * * * * * *

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.

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%

Percentage of Patients

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 Months

Device 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

• r 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]

Favors MitraClip + GDMT Favors GDMT alone

24-Month All-cause Mortality

• r First HF Hospitalization (ii)

0.2 0.5 1 1.5 2.5

Favors MitraClip + GDMT Favors GDMT alone

24-Month All-cause Mortality

• r 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] 0.28 3+ (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] 0.21 Tier 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 Alone MitraClip + 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

• f 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
• utcomes 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.