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)
Disclosure Statement 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. 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 100% MitraClip + GDMT HF Hospitalization (%) HR [95% CI] = All-cause Mortality or GDMT alone 80% 0.57 [0.45-0.71] P<0.001 67.9% 60% 45.7% 40% NNT (24 mo) = 20% 4.5 [95% CI 3.3, 7.2] 0% 0 3 6 9 12 15 18 21 24 Time After Randomization (Months) No. at Risk: MitraClip + GDMT 302 264 238 215 194 154 145 126 97 GDMT alone 312 244 205 174 153 117 90 75 55 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 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 Ineligible N=911 Inadequate MR or DMR (n=244) Echo criteria not met (n=255) Subjects with screening TTEs and Not treated with GDMT (n=79) meeting all eligibility requirements All inclusion criteria not met (n=85) for enrollment in COAPT Exclusion criteria present (n=34) Incomplete screening/other (n=419) N=665 Secondary MR, Severity 3+ or 4+ (graded by 1 of 3 criteria) Randomized Roll-in subjects subjects N=614 N=51
Inclusion Flowchart (ii) Secondary MR, Severity 3+ or 4+ (graded by 1 of 3 criteria) Tier 1 Tier 3 Tier 2 EROA ≥ 0.3 cm 2 EROA 0.2 cm 2 - <0.3 cm 2 EROA not measured or <0.2 cm 2 With at least 2 of the following: or With any 1 of the following: • RV ≥ 45 ml/beat • RV ≥ 45 ml/beat PV systolic flow reversal • RF ≥ 40% • RF ≥ 40% • VC width ≥ 0.5 cm • VC width ≥ 0.5 cm • PISA radius > 0.9 cm, but CW of MR jet not done N=570 (85.7%) N=70 (10.5%) • Large (≥ 6.0 cm) holosystolic jet wrapping around LA • Peak E velocity ≥ 150 cm/s N=25 (3.8%)
Baseline Echo Characteristics (i) Device Group Control Group P-value (N=302) (N=312) 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)
Baseline Echo Characteristics (ii) Device Group Control Group P-value (N=302) (N=312) 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 cm 2 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 (iii) Device Group Control Group P-value (N=302) (N=312) 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)
Change in LV Volumes Over Time Left Ventricular End Diastolic Volume ( LVEDV ) Paired measures, follow-up minus baseline 75 Mean ± SE LVEDV (mL) from Baseline * * Adjusted Change in 50 Device y (Device) * 25 Control y (Control) 0 * * * -25 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 LV Volumes Over Time Left Ventricular End Systolic Volume ( LVESV ) Paired measures, follow-up minus baseline 125 Mean ± SE LVESV (mL) from Baseline * 100 Adjusted Change in * 75 Device Device y (Device) 50 * Control Control y (Control) * * 25 * 0 * * -25 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 Left Ventricular Ejection Fraction ( LVEF ) Paired measures, follow-up minus baseline 5 Mean ± SE LVEF (%) from Baseline Adjusted Change in 0 * * * * Device y (Device) * -5 * * Control y (Control) * * -10 -15 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.
Overall MR Severity Baseline 30 Days 6 Months 12 Months 18 Months 24 Months All P<0.001 Device Control Device Control Device Control Device Control Device Control Device Control MR ≤2+ 0.0% 0.0% 92.7% 34.2% 93.8% 38.1% 94.8% 46.9% 95.0% 40.4% 99.1% 43.4% 100% 0.1% 1.5% 0.7% 0.9% 1.7% 4.3% 4.3% 4.6% 5.9% 15.8% Percentage of Patients 18.4% 18.9% 19.7% 21.9% 28.4% 19.9% 19.8% 25.7% 80% 27.1% 44.7% 51.0% ≤1+ 34.3% 40.8% 60% 41.2% 42.2% 2+ 37.4% 3+ 40% 77.2% 75.2% 72.9% 69.0% 66.7% 4+ 27.6% 35.4% 55.3% 28.1% 49.0% 28.9% 20% 26.1% 15.8% 12.3% 11.4% 9.2% 8.2% 0% N=302 N=311 N=273 N=257 N=240 N=218 N=210 N=175 N=141 N=114 N=114 N=76 D=0 D=0 D=10 D=10 D=32 D=40 D=59 D=75 D=69 D=99 D=78 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
MR Changes From Baseline to 12 Months Device Group Control Group P-value (N=302) (N=312) 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 Control Group P-value (N=302) (N=312) 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
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