Echocardiographic Outcomes in Heart Failure Patients with Secondary Mitral Regurgitation: COAPT Trial

This study presents the echocardiographic outcomes from the COAPT trial focusing on heart failure patients with secondary mitral regurgitation. The trial evaluated the impact of MitraClip therapy in conjunction with guideline-directed medical therapy compared to medical therapy alone. Results showed significant reductions in death or heart failure hospitalization with the combined treatment approach. The study also highlights the challenges in assessing the severity of secondary mitral regurgitation due to anatomical complexities. Furthermore, the objectives include describing echocardiographic grading criteria, population characteristics, and predictors of clinical outcomes.

• Echocardiography
• Heart Failure
• Mitral Regurgitation
• COAPT Trial
• Cardiology

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1. 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)

2. 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

3. 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.

4. Death or HF Hospitalization 100% MitraClip + GDMT GDMT alone HR [95% CI] = 0.57 [0.45-0.71] P<0.001 HF Hospitalization (%) All-cause Mortality or 80% 67.9% 60% 45.7% 40% NNT (24 mo) = 4.5 [95% CI 3.3, 7.2] 20% 0% 0 3 6 9 12 15 18 21 24 Time After Randomization (Months) No. at Risk: MitraClip + GDMT GDMT alone 302 312 264 244 238 205 215 174 194 153 154 117 145 90 126 75 97 55 Stone GW et al. NEJM 2018;379:2307-18

5. 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.

6. 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)

7. 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)

8. 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

9. 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 meeting all eligibility requirements for enrollment in COAPT N=665 Not treated with GDMT (n=79) All inclusion criteria not met (n=85) Exclusion criteria present (n=34) Incomplete screening/other (n=419) Secondary MR, Severity 3+ or 4+ (graded by 1 of 3 criteria) Randomized subjects N=614 Roll-in subjects N=51

10. Inclusion Flowchart (ii) Secondary MR, Severity 3+ or 4+ (graded by 1 of 3 criteria) Tier 1 Tier 3 Tier 2 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%) EROA 0.3 cm2 or PV systolic flow reversal 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=570 (85.7%) N=70 (10.5%)

11. 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 44.0 13.4 (253) 44.6 14.0 (275) RVSP, mmHg 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)

12. Baseline Echo Characteristics (ii) 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 59.7 21.0 (288) 59.9 23.5 (302) Reg. volume, PISA ml 0.91 Vena contracta, cm 0.58 0.12 (277) 0.58 0.12 (293) 0.88 110.6 28.7 (280) 109.4 24.9 (286) Peak E, cm/sec 0.60

13. Baseline Echo Characteristics (iii) Device Group (N=302) Control Group (N=312) P-value Pulmonary Vein Flow - None (0) - Mild (1+) - Moderate (2+) - Moderate to severe (3+) - Severe (4+) MR Color Flow Jet - None (0) - Mild (1+) - Moderate (2+) - Moderate to severe (3+) - Severe (4+) 0.02 0.0% (0/240) 0.4% (1/240) 12.9% (31/240) 30.0% (72/240) 56.7% (136/240) 0.0% (0/234) 0.9% (2/234) 12.4% (29/234) 42.7% (100/234) 44.0% (103/234) 0.18 0.0% (0/302) 0.0% (0/302) 6.0% (18/302) 43.0% (130/302) 51.0% (154/302) 0.0% (0/312) 0.0% (0/312) 6.7% (21/312) 47.8% (149/312) 45.5% (142/312)

14. Change in LV Volumes Over Time Left Ventricular End Diastolic Volume (LVEDV) Paired measures, follow-up minus baseline Mean SE 75 * LVEDV (mL) from Baseline * Adjusted Change in 50 y (Device) Device Control * 25 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.

15. Change in LV Volumes Over Time Left Ventricular End Systolic Volume (LVESV) Paired measures, follow-up minus baseline Mean SE 125 LVESV (mL) from Baseline * 100 Adjusted Change in * 75 y (Device) Device Device Control y (Control) Control 50 * * * 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.

16. Change in Ejection Fraction Over Time Left Ventricular Ejection Fraction (LVEF) Paired measures, follow-up minus baseline Mean SE 5 LVEF (%) from Baseline Adjusted Change in 0 * * * * y (Device) Device Control * -5 * * 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.

17. Overall MR Severity Baseline 30 Days 6 Months 12 Months 18 Months 24 Months All P<0.001 Device 0.0% Control 0.0% 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+ 100% 0.1% 0.9% 0.7% 1.5% 1.7% 4.3% 4.3% 4.6% 5.9% 15.8% 18.4% Percentage of Patients 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% 4+ 66.7% 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=210 D=59 N=175 D=75 N=141 D=69 N=114 D=99 N=114 D=78 N=76 D=115 N=302 D=0 N=311 D=0 N=273 D=10 N=257 D=10 N=240 D=32 N=218 D=40 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

18. MR Changes From Baseline to 12 Months Device Group (N=302) MR Severity, n (%) - Improved by 2 grades 84.1% (243/289) - Improved by 1 grade 11.1% (32/289) - No change 4.8% (14/289) - Worsened by 1 grade 0.0% (0/289) Pulmonary vein flow, n (%) - Improved 83.6% (107/128) - No change 14.8% (19/128) - Worsened 1.6% (2/128) Vena contracta, cm -0.14 0.17 (110) MR color flow jet - Improved 94.1% (272/289) - No change 4.8% (14/289) - Worsened 1.0% (3/289) Control Group (N=312) P-value <0.0001 15.9% (44/277) 40.4% (112/277) 36.8% (102/277) 6.9% (19/277) <0.0001 39.6% (53/134) 40.3% (54/134) 20.1% (27/134) -0.03 0.16 (186) <0.0001 <0.0001 54.9% (152/277) 34.3% (95/277) 10.8% (30/277)

19. 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

20. 24-Month All-cause Mortality or First HF Hospitalization (i) 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) < 30% (median: n=274) > 40% (n=103) 40% (n=472) LVEDV (median) 181 mL (n=288) < 181 mL (n=287) 44.1% (62) 45.8% (55) 49.7% (22) 43.8% (95) 60.5% (84) 77.6% (98) 53.5% (26) 71.8% (156) 0.61 [0.44, 0.85] 0.46 [0.33, 0.64] 0.70 [0.39, 1.23] 0.50 [0.39, 0.65] 0.29 0.26 48.3% (63) 41.5% (54) 68.0% (92) 68.5% (90) 0.57 [0.41, 0.79] 0.49 [0.35, 0.69] 0.52 LVESV (median) 46.8% (60) 43.1% (57) 71.1% (97) 65.7% (85) 0.51 [0.37, 0.71] 0.55 [0.39, 0.77] 124 mL (n=288) < 124 mL (n=287) LV Stroke Volume (median) 49 mL (n=286) < 49 mL (n=289) LVEDD (median) 6.1 cm (n=340) < 6.1 cm (n=268) 0.83 46.0% (60) 44.3% (59) 65.0% (88) 69.5% (89) 0.64 [0.46, 0.89] 0.49 [0.35, 0.69] 0.30 48.4% (76) 41.9% (52) 71.2% (110) 64.3% (79) 0.56 [0.41, 0.75] 0.56 [0.39, 0.79] 0.94 0.2 0.5 1 1.5 2.5 Favors MitraClip + GDMT Favors GDMT alone

21. 24-Month All-cause Mortality or First HF Hospitalization (ii) 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) 4+ (n=293) PISA Radius (median) 0.87 cm (n=306) < 0.87 cm (n=294) 36.9% (50) 53.4% (78) 64.4% (98) 71.4% (91) 0.48 [0.34, 0.68] 0.62 [0.45, 0.83] 0.30 48.2% (72) 42.0% (52) 66.5% (92) 67.1% (94) 0.57 [0.42, 0.78] 0.54 [0.39, 0.76] 0.86 EROA, PISA (median) 0.37 cm2 (n=309) < 0.37 cm2 (n=282) Reg Vol, PISA (median) 23 mL (n=138) < 23 mL (n=122) Reg Fraction (median) 36% (n=135) < 36% (n=124) 49.8% (75) 37.9% (45) 73.7% (102) 60.4% (81) 0.52 [0.38, 0.70] 0.54 [0.37, 0.78] 0.91 45.1% (30) 40.1% (19) 62.2% (38) 73.5% (47) 0.50 [0.31, 0.81] 0.43 [0.25, 0.74] 0.71 45.7% (28) 40.9% (21 70.5% (43) 67.1% (42) 0.44 [0.27, 0.71] 0.50 [0.29, 0.85] 0.75 0.2 0.5 1 1.5 2.5 Favors MitraClip + GDMT Favors GDMT alone

22. 24-Month All-cause Mortality 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) < 0.57 cm (n=275) Pulmonary Vein Flow 0 / 1+ / 2+ (n=63) 3+ (n=172) 4+ (n=238) TR severity 1+ (n=501) 2+ (n=98) Peak E (median) 109 cm/sec (n=292) < 109 cm/sec (n=274) RVSP (median) 43 mmHg (n=276) < 43 mmHg (n=252) Tier of Echo Eligibility Tier 1 (n=530) Tier 2 (n=61) Tier 3 (n=23) 46.8% (65) 44.4% (54) 69.3% (93) 66.4% (86) 0.53 [0.38, 0.73] 0.59 [0.42, 0.83] 0.62 34.8% (10) 42.1% (28) 49.5% (63) 62.7% (19) 72.5% (64) 66.5% (61) 0.41 [0.19, 0.89] 0.43 [0.28, 0.68] 0.65 [0.46, 0.92] 0.28 44.7% (107) 49.9% (20) 64.5% (143) 81.0% (40) 0.61 [0.47, 0.78] 0.43 [0.25, 0.74] 0.21 49.7% (68) 41.8% (52) 73.7% (98) 58.5% (73) 0.52 [0.38, 0.72] 0.69 [0.48, 0.99] 0.25 55.8% (69) 36.1% (40) 76.8% (103) 53.9% (61) 0.62 [0.45, 0.84] 0.58 [0.39, 0.86] 0.79 47.2% (117) 17.4% (4) 50.0% (7) 67.0% (161) 67.9% (23) 70.0% (5) 0.58 [0.46, 0.74] 0.23 [0.08, 0.68] 0.80 [0.25, 2.54] 0.21 0.2 0.5 1 1.5 2.5 Favors MitraClip + GDMT Favors GDMT alone

23. Predictors of 24-Month Mortality or First HF Hospitalization Multivariable Cox regression MitraClip + GDMT GDMT Alone Hazard Ratio [95% CI] Hazard Ratio [95% CI] P-Value P-Value 1.02 [1.01, 1.04] 0.005 RVSP (mmHg) 1.60 [1.07, 2.39] 0.022 TR Grade ( 2+ vs 1+) 1.12 [1.02, 1.23] 0.020 STS Repl Score 0.98 [0.96, 1.00] 0.027 LVEF (%) 1.00 [1.00, 1.01] 0.07 LVEDV (mL) 1.01 [1.00, 1.02] 0.032 RVSP (mmHg) 0.64 [0.37, 1.08] 0.09 Sex (Female vs Male) 3.15 [1.08, 9.21] 0.036 EROA, PISA (cm2) 2.56 [0.79, 8.26] 0.12 EROA, PISA (cm2) 1.07 [0.98, 1.18] 0.14 STS Repl Score 0.70 [0.43, 1.13] 0.15 Isch vs Non-Isch CM 0.99 [0.97, 1.01] 0.24 Age (years) 0.95 [0.88, 1.04] 0.26 STS Repair Score 0.96 [0.87, 1.07] 0.47 STS Repair Score 1.01 [0.98, 1.03] 0.56 LVEF (%) 0.92 [0.62, 1.36] 0.66 Isch vs Non-Isch CM 1.01 [0.98, 1.03] 0.57 Age (years) 1.00 [1.00, 1.00] 0.84 LVEDV (mL) 0.90 [0.51, 1.61] 0.73 TR Grade ( 2+ vs 1+) 0.97 [0.64, 1.46] 0.87 Sex (Female vs Male)

24. 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).

25. 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).

26. 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.

27. 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.