Burden of Mitral Regurgitation (MR) in the US Why is This Important?

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1 Secondary (Functional) Mitral Regurgitation as a Target for Heart Failure Therapy William T. Abraham, MD, FACP, FACC, FAHA, FESC, FRCP Professor of Medicine, Physiology, and Cell Biology Chair of Excellence in Cardiovascular Medicine Director, Division of Cardiovascular Medicine Associate Dean for Clinical Research Director, Clinical Trials Management Organization Deputy Director, Davis Heart & Lung Research Institute The Ohio State University, Columbus, Ohio Burden of Mitral Regurgitation (MR) in the US Why is This Important? Major and growing public health problem resulting in substantial morbidity and mortality Greater than 4.1 million Americans with MR Prevalence is age-dependent, affecting 9.3% of those aged greater than 75 years Presence of MR is associated with substantial patient morbidity and mortality Hospitalization-free survival correlates inversely with MR severity Mortality increased roughly two-fold by presence of MR Nkomo VT, et al., Lancet, 2006; 368: Suri R, et al., JAMA 2013; 310: Nishimura R, et al., J Am Coll Cardiol 2014; 63:

2 Two Types of Mitral Regurgitation Incompetent mitral valve closure Systolic retrograde blood flow from the LV into the LA Primary: Anatomic abnormality of the mitral valve Leaflets Subvalvular apparatus Chordae and papillary muscles Secondary : LV dilation; secondary to ischemic and nonischemic heart disease Leads to mitral annular dilation Incomplete coaptation of the mitral valve Why is this Topic Important to Those Who Care for Heart Failure Patients? About 40% of heart failure (HF) patients have moderate or severe secondary (functional) MR Secondary MR is associated with a poor prognosis in HF patients Secondary MR worsens outcomes in both ischemic and nonischemic cardiomyopathy patients Mitral regurgitation contributes to heart failure disease progression, symptoms, and prognosis via increased ventricular loading 2

3 Secondary MR Worsens Heart Failure Outcomes Hospitalization-free Survival (%) 100 Hospitalization-free survival decreased with increased MR severity P< Years No MR (40%) Mild/Mod MR (25%) Severe MR (7%) Transplant-free Survival (%) 100 Transplant-free survival decreased with increased MR severity P< Grade IV (46.5 ±6.7%) No MR & Grade I (82.7 ±3.1%) Grade II (64.4 ±4.9%) Grade III (58.5 ±4.6%) Days 1.Rossi A, et al. Heart 2011; 97: ; 2. Bursi F, et al. Eur J Heart Fail 2010; 12: Mitral Regurgitation (MR) Treatment Primary MR: Disorder of the Mitral Valve Apparatus (annulus, leaflets, chords, papillary muscle Functional MR: Leaflets appear normal, MR due to abnormal LV geometry Valve makes the Ventricle Sick Ventricle makes the Valve Sick Mechanical Solution: Open Surgical / Transcatheter repair /replacement Medical treatment for LV dysfunction Mechanical reduction of MR? 3

4 Rationale for Treating Secondary MR Vicious Cycle of LV Dilation / Dysfunction Increased Ventricular Load Pathological Remodeling (Ventricle) Mitral Regurgitation (Valve) Increased Ventricular Volume How are Patients with Isolated Secondary MR Treated Today? Courtesy of M. Mack MD, FACC, Baylor Scott & White Health 4

5 Pre-COAPT View of Secondary MR Chronic severe secondary MR adds volume overload to a decompensated LV and worsens prognosis There are only sparse data to indicate that correcting MR prolongs life or improves symptoms over an extended time Percutaneous MR repair provides a less invasive alternative to surgery but is not approved for clinical use for this indication in the United States O Gara PT, et al. JACC 2017 Pre-COAPT Secondary MR Management Optimize guideline-directed heart failure medical therapies and CRT, when indicated Consider advanced heart failure therapies for progressive / end-stage heart failure, e.g. left ventricular assist device implantation or cardiac transplantation When all else fails, consider end-of-life (hospice) care And then the world changed on September 23, 2018 O Gara PT, et al. JACC

6 Published online September 23, 2018 at NEJM.org The COAPT Trial Design Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation A parallel-controlled, open-label, multicenter trial in ~610 patients with heart failure and moderate-to-severe (3+) or severe (4+) secondary MR who remained symptomatic despite maximally-tolerated GDMT Randomize 1:1* MitraClip + GDMT N=305 GDMT alone N=305 *Stratified by cardiomyopathy etiology (ischemic vs. non-ischemic) and site Principal Investigators: Gregg Stone, Michael Mack, William Abraham, Joann Lindenfeld, 6

7 Transvascular Edge-to-Edge Mitral Valve Repair Mitral Regurgitation MitraClip Device Implanted COAPT Study Enrollment and Randomization 1576 pts with HF and MR considered for enrollment between September 25 th, 2012 and June 23 th, 2017 at 89 centers in the US and Canada Roll-in cases N=51 at 34 sites Eligible for enrollment N=665 Randomized N=614 at 78 sites Ineligible N=911 Reasons for exclusion Inadequate 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) MitraClip + GDMT N=302 GDMT alone N=312 Stone GW, et al. online September 23, 2018 at NEJM.org 7

8 COAPT Results The trial met its primary efficacy endpoint all (cumulative) heart failure hospitalizations through 24 months (HR 0.53; 95% CI 0.40 to 0.70; P<0.001) All 10 pre-specified secondary powered endpoints were met, e.g. Reduction in mitral regurgitation and LVEDV Improvement in quality of life, exercise capacity, and functional status Reduction in all-cause mortality through 24 months (HR 0.62; 95% CI 0.46 to 0.82; P<0.001) The rate of adverse events was consistent with known rates for this procedure (primary safety endpoint was met) Stone GW, et al. online September 23, 2018 at NEJM.org COAPT Primary Efficacy Endpoint Cumulative Heart Failure Hospitalizations Cumulative Total Heart Failure Hospitalizations (n) No. at Risk: Device group Control group Device group Control group NNT (24 mo) = 3.1 [95% CI 1.9, 8.2] Time After Randomization (Months) 283 in 151 patients 160 In 92 patients Hazard ratio, 0.53 [95% CI, ] P< Stone GW, et al. online September 23, 2018 at NEJM.org 8

9 COAPT Freedom From Device-Related Complications Freedom from Device-related Complications (%) 100% 80% 60% 40% 20% 96.6% 94.8% (lower 95% confidence limit) 88% (performance goal) No. at Risk: Device group 0% Time After Randomization (Months) Stone GW, et al. online September 23, 2018 at NEJM.org COAPT Powered Secondary Endpoints - Tested in hierarchical order 1 - P-value 1. MR grade 2+ at 12 months < All-cause mortality at 12 months 2 < Death and all HF hospitalization through 24 months (Finkelstein-Schoenfeld) < Change in QOL (KCCQ) from baseline to 12 months < Change in 6MWD from baseline to 12 months < All-cause hospitalizations through 24 months NYHA class I or II at 12 months < Change in LVEDV from baseline to 12 months All-cause mortality at 24 months < Death, stroke, MI, or non-elective CV surgery for device-related compls at 30 days 3 < All powered for superiority unless otherwise noted; 2 Powered for noninferiority of the device vs. the control group; 3 Powered for noninferiority against an objective performance goal 9

10 COAPT Secondary Endpoint All-Cause Mortality All-cause Mortality (%) No. at Risk: Device group Control group 100% 80% 60% 40% Device group Control group Stone GW, et al. online September 23, 2018 at NEJM.org Hazard ratio, 0.62 [95% CI, ] P< % 20% NNT (24 mo) = 5.9 [95% CI 3.9, 11.7] 0% Time After Randomization (Months) % Change in KCCQ from Baseline to 12 Months KCCQ Summary Score GDMT alone 52.9 ± ±22.7 Baseline MitraClip + GDMT 49.6 ± ±28.6 n=228 n=236 n=228 n= Months KCCQ change from BL to 12 mo ( LSM SE) Adjusted change* 12.5 ±1.8 P<0.001 ± *Ancova 10

11 Subgroups: 24-Month Death or HF Hospitalization Subgroup MitraClip + GDMT GDMT alone HR [95% CI] HR [95% CI] P [Int] All patients Age (median) 74 years (n=317) <74 years (n=297) Sex Female (n=221) Male (n=393) Etiology of cardiomyopathy Ischemic (n=373) Non-ischemic (n=241) Prior CRT Yes (n=224) No (n=390) HF hospitalization within the prior year Yes (n=407) No (n=207) Baseline NYHA class I or II (n=240) III (n=322) IV (n=51) STS replacement score 8% (n=262) <8% (n=352) Surgical risk status* High (n=423) Not high (n=188) Baseline MR grade 3+ (n=320) 4+ (n=293) Baseline LVEF 30% (median; n=301) <30% (median; n=274) >40% (n=103) 40% (n=472) Baseline LVEDV (median) 181 ml (n=288) <181 ml (n=287) 45.7% (129) 52.1% (78) 37.8% (51) 43.2% (39) 47.1% (90) 48.1% (84) 41.1% (45) 50.2% (55) 42.9% (74) 44.7% (86) 47.6% (43) 41.1% (50) 46.6% (67) 68.3% (12) 54.1% (65) 39.2% (64) 49.7% (95) 35.8% (32) 37.5% (51) 53.4% (78) 44.1% (62) 46.4% (56) 49.7% (22) 44.2% (96) 48.9% (43) 41.5% (54) 67.9% (191) 70.2% (100) 65.3% (91) 59.4% (66) 73.0% (125) 70.0% (116) 65.2% (75) 68.4% (69) 67.4% (122) 67.9% (126) 67.8% (65) 66.9% (65) 65.3% (99) 84.4% (26) 71.4% (88) 65.0% (103) 71.5% (140) 58.7% (51) 65.3% (100) 71.4% (91) 61.2% (85) 77.8% (99) 56.2% (27) 71.9% (157) 68.0% (92) 69.5% (92) 0.57 [0.45, 0.71] 0.65 [0.48, 0.88] 0.47 [0.33, 0.66] 0.60 [0.40, 0.89] 0.54 [0.41, 0.71] 0.57 [0.43, 0.76] 0.54 [0.37, 0.78] 0.62 [0.44, 0.89] 0.53 [0.39, 0.71] 0.56 [0.42, 0.73] 0.59 [0.40, 0.86] 0.56 [0.39, 0.81] 0.61 [0.44, 0.83] 0.56 [0.28, 1.12] 0.64 [0.46, 0.88] 0.51 [0.37, 0.70] 0.58 [0.45, 0.75] 0.51 [0.33, 0.80] 0.48 [0.34, 0.67] 0.62 [0.45, 0.83] 0.60 [0.43, 0.84] 0.46 [0.33, 0.64] 0.67 [0.38, 1.17] 0.50 [0.39, 0.65] 0.58 [0.42, 0.80] 0.48 [0.34, 0.67] KM time-to-first event rates *Central eligibility committee assessment Favors MitraClip + GDMT Favors GDMT alone Mitra-FR Results The trial did not meet its primary efficacy endpoint a composite of death from any cause or unplanned hospitalization for heart failure through 12 months Neither component of the primary endpoint was improved by percutaneous mitral valve repair A large amount of follow-up data on functional status, natriuretic peptide level, echocardiographic outcomes, and quality of life were missing at 12 months, making it difficult to assess the the effects percutaneous mitral valve repair on these endpoints The rate of adverse events was consistent with known rates for this procedure Obadia JF, et al. online August 27, 2018, 2018 at NEJM.org 11

12 Mitra-FR Primary Endpoint Death from Any Cause or Unplanned HF Hospitalization Obadia JF, et al. online August 27, 2018, 2018 at NEJM.org Important Mitra-FR and COAPT Differences Mitra-FR COAPT N (Planned / Actual) 288 / / 614 LVEF / LVESD 15-40% / no restriction 20-50% / 70 mm FMR Definition GDMT (Baseline) GDMT (Follow-Up) Other criteria Primary Endpoint Regurgitant volume > 30 ml or EROA > 20 mm 2 3+ or 4+ Determined by local investigator Medication changes post-randomization not collected History of HF hospitalization in past 12 months All-cause mortality and unplanned HF hospitalization through 12 months (first event) Determined by Central Eligibility Committee with documentation of titration to highest tolerated GDMT doses Medication changes (including dosage changes) required clinical/medical justification and were thoroughly documented History of HF hospitalization in past 12 months and / or elevated BNP or NTproBNP level Recurrent HF hospitalizations thorough 24 months (all events) 12

13 Important Mitra-FR and COAPT Differences Mitra-FR COAPT N (Planned / Actual) 288 / / 614 LVEF / LVESD Mean LVEDVI 135 ml/m 2 Mean LVEDVI 101 ml/m 2 FMR Definition GDMT (Baseline) GDMT (Follow-Up) Other criteria Primary Endpoint Regurgitant volume > 30 ml/min or EROA > 20 mm 2 3+ or 4+ Determined by local investigator Medication changes post-randomization not collected History of HF hospitalization in past 12 months All-cause mortality and unplanned HF hospitalization through 12 months (first event) Determined by Central Eligibility Committee with documentation of titration to highest tolerated GDMT doses Medication changes (including dosage changes) required clinical/medical justification and were thoroughly documented History of HF hospitalization in past 12 months and / or elevated BNP or NTproBNP level Recurrent HF hospitalizations thorough 24 months (all events) Important Mitra-FR and COAPT Differences Mitra-FR COAPT N (Planned / Actual) 288 / / 614 LVEF / LVESD 15-40% / no restriction 20-50% / 70 mm FMR Definition Mean EROA 31 mm 2 ; 51% < 30 mm 2 Mean EROA 41 mm 2 ; 13% < 30 mm 2 GDMT (Baseline) GDMT (Follow-Up) Other criteria Primary Endpoint Determined by local investigator Medication changes post-randomization not collected History of HF hospitalization in past 12 months All-cause mortality and unplanned HF hospitalization through 12 months (first event) Determined by Central Eligibility Committee with documentation of titration to highest tolerated GDMT doses Routine medication changes were discouraged; changes required documented changes in clinical condition; all medication changes were collected History of HF hospitalization in past 12 months and / or elevated BNP or NTproBNP level Recurrent HF hospitalizations thorough 24 months (all events) 13

14 Important Mitra-FR and COAPT Differences Mitra-FR COAPT N (Planned / Actual) 288 / / 614 LVEF / LVESD 15-40% / no restriction 20-50% / 70 mm FMR Definition GDMT (Baseline) GDMT (Follow-Up) Other criteria Primary Endpoint Regurgitant volume > 30 ml/min or ERO > 20 mm 2 3+ or 4+ Determined by local investigator Medication changes post-randomization not collected History of HF hospitalization in past 12 months All-cause mortality and unplanned HF hospitalization through 12 months (first event) Determined by Central Eligibility Committee with documentation of titration to highest tolerated GDMT doses Medication changes (including dosage changes) required clinical/medical justification and were thoroughly documented History of HF hospitalization in past 12 months and / or elevated BNP or NTproBNP level Recurrent HF hospitalizations thorough 24 months (all events) COAPT Impact of EROA and LVEDV: EROA >40 mm 2 All-cause mortality or HF hospitalization through 12 months LVEDVI >96 ml/m 2 (N=130; 23.7%) LVEDVI 96 ml/m 2 (N=92; 16.8%) 14

15 COAPT Impact of EROA and LVEDV: EROA >30-40 mm 2 All-cause mortality or HF hospitalization through 12 months LVEDVI >96 ml/m 2 (N=88; 16.1%) LVEDVI 96 ml/m 2 (N=131; 23.9%) COAPT Impact of EROA and LVEDV: EROA 30 mm 2 All-cause mortality or HF hospitalization through 12 months LVEDVI >96 ml/m 2 (N=56; 10.2%) LVEDVI 96 ml/m 2 (N=51; 9.3%) 15

16 COAPT Major Changes in HF Meds w/i 12 Months MitraClip + GDMT (n=302) GDMT alone (n=312) P value ACEI, ARB or ARNI - dose by >50% or discontinue 6.6% 4.8% dose by >100% or new drug started 7.6% 7.4% 0.91 Beta-blocker - dose by >50% or discontinue 5.3% 5.1% dose by >100% or new drug started 8.6% 3.8% 0.01 Mineralocorticoid receptor antagonist - dose by >50% or discontinue 0.7% 0.6% dose by >100% or new drug started 5.3% 2.6% 0.08 Nitrates - dose by >50% or discontinue 0.0% 0.0% dose by >100% or new drug started 1.0% 1.9% 0.51 Hydralazine - dose by >50% or discontinue 1.0% 0.0% dose by >100% or new drug started 4.3% 3.8% 0.77 Conclusions Reduction of secondary MR in symptomatic heart failure patients improves clinical outcomes (morbidity and mortality), as well as multiple patient-centered endpoints such as quality of life Size of the left ventricle appears to matter Definition of secondary MR severity appears to matter Larger ventricle / less MR = non-responder Optimally tolerated GDMT at baseline is important in maximizing the efficacy of secondary MR reduction 16

17 Final Conclusion Based on an understanding of the role that FMR plays in heart failure disease progression, symptoms, and clinical outcomes and on the COAPT trial results, transcatheter mitral valve repair reduces the rate of hospitalizations for heart failure, is safe, and improves survival, quality of life, and functional capacity in heart failure patients with moderate-to-severe or severe (Grade 3+ or 4+) secondary mitral regurgitation who remain symptomatic despite guidelinedirected medical therapy MitrClip is not currently approved for the treatment FMR in the U.S. 17