10/26/2018 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: 1005-1011 Suri R, et al., JAMA 2013; 310:609-616 Nishimura R, et al., J Am Coll Cardiol 2014; 63:2438-2488
Transcript
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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 USWhy 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: 1005-1011Suri R, et al., JAMA 2013; 310:609-616Nishimura R, et al., J Am Coll Cardiol 2014; 63:2438-2488
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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
• Subvalvularapparatus
• Chordae and papillary muscles
Secondary :LV dilation; secondary to ischemic and non-ischemic 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 non-ischemic cardiomyopathy patients
• Mitral regurgitation contributes to heart failure disease progression, symptoms, and prognosis via increased ventricular loading
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51.Rossi A, et al. Heart 2011; 97:1675-1680; 2. Bursi F, et al. Eur J Heart Fail 2010; 12:382-388
Mild/Mod MR(25%)
Hospitalization-free survival decreased with increased MR severity1
100
80
60
40
20
0
Hos
pita
lizat
ion-
free
Sur
viva
l (%
)
Years
0 1 2 3 4 5 6 7
P<0.01
No MR(40%)
Severe MR (7%)
Secondary MR Worsens Heart Failure Outcomes
Transplant-free survival decreased with increased MR severity2
100
90
80
70
60
50
40Tra
nspl
ant-
free
Sur
viva
l (%
)Days
0 500 1000 1500 2000
Grade IV(46.5 ±6.7%)
Grade III(58.5 ±4.6%)
Grade II(64.4 ±4.9%)
No MR & Grade I(82.7 ±3.1%)
P<0.0001
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 ?
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
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Rationale for Treating Secondary MRVicious Cycle of LV Dilation / Dysfunction
PathologicalRemodeling
(Ventricle)
MitralRegurgitation
(Valve)
IncreasedVentricular
Load
IncreasedVentricular
Volume
How are Patients with Isolated Secondary MR Treated Today?
Courtesy of M. Mack MD, FACC, Baylor Scott & White Health
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• 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
Pre-COAPT View of Secondary MR
O’Gara PT, et al. JACC 2017
• 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
Pre-COAPT Secondary MR Management
O’Gara PT, et al. JACC 2017
• And then… the world changed on September 23, 2018
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Published online September 23, 2018 at NEJM.org
The COAPT Trial DesignCardiovascular 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*
GDMT aloneN=305
MitraClip + GDMTN=305
*Stratified by cardiomyopathy etiology (ischemic vs. non-ischemic) and site
Principal Investigators: Gregg Stone, Michael Mack, William Abraham, Joann Lindenfeld,
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Transvascular Edge-to-Edge Mitral Valve Repair
Mitral Regurgitation MitraClip Device Implanted
COAPT Study Enrollment and Randomization1576 pts with HF and MR considered for enrollment between September
25th, 2012 and June 23th, 2017 at 89 centers in the US and Canada
MitraClip + GDMTN=302
GDMT aloneN=312
Reasons for exclusionInadequate 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)
RandomizedN=614 at 78 sites
IneligibleN=911
Roll-in casesN=51 at 34 sites
Eligible for enrollment N=665
Stone GW, et al. online September 23, 2018 at NEJM.org
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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
Stone GW, et al. online September 23, 2018 at NEJM.org
COAPT Powered Secondary Endpoints
1All powered for superiority unless otherwise noted; 2Powered for noninferiority of the device vs. the control group; 3Powered for noninferiority against an objective performance goal
P-value
1. MR grade 2+ at 12 months <0.001
2. All-cause mortality at 12 months2 <0.001
3. Death and all HF hospitalization through 24 months (Finkelstein-Schoenfeld) <0.001
4. Change in QOL (KCCQ) from baseline to 12 months <0.001
5. Change in 6MWD from baseline to 12 months <0.001
6. All-cause hospitalizations through 24 months 0.03
7. NYHA class I or II at 12 months <0.001
8. Change in LVEDV from baseline to 12 months 0.003
9. All-cause mortality at 24 months <0.001
10. Death, stroke, MI, or non-elective CV surgery for device-related compls at 30 days3 <0.001
- Tested in hierarchical order1 -
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COAPT Secondary EndpointAll-Cause Mortality
Stone GW, et al. online September 23, 2018 at NEJM.org
All-
cau
se M
ort
alit
y (%
)
0%
20%
40%
60%
80%
100%
Time After Randomization (Months)0 3 6 9 12 15 18 21 24
KM time-to-first event rates*Central eligibility committee assessment
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
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Mitra-FR Primary EndpointDeath from Any Cause or Unplanned HF Hospitalization
Obadia JF, et al. online August 27, 2018, 2018 at NEJM.org
Mitra-FR COAPT
N (Planned / Actual) 288 / 307 610 / 614
LVEF / LVESD 15-40% / no restriction 20-50% / ≤ 70 mm
FMR DefinitionRegurgitant volume > 30 mL or
EROA > 20 mm2 3+ or 4+
GDMT (Baseline) Determined by local investigatorDetermined by Central Eligibility
Committee with documentation of titration to highest tolerated GDMT doses
COAPT Major Changes in HF Meds w/i 12 MonthsMitraClip + GDMT
(n=302)GDMT alone
(n=312)P value
ACEI, ARB or ARNI- ⇓ dose by >50% or discontinue 6.6% 4.8% 0.33 - ⇑ dose by >100% or new drug started 7.6% 7.4% 0.91
Beta-blocker- ⇓ dose by >50% or discontinue 5.3% 5.1% 0.92 - ⇑ 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% 1.00 - ⇑ dose by >100% or new drug started 5.3% 2.6% 0.08
Nitrates- ⇓ dose by >50% or discontinue 0.0% 0.0% 1.00 - ⇑ dose by >100% or new drug started 1.0% 1.9% 0.51
Hydralazine- ⇓ dose by >50% or discontinue 1.0% 0.0% 0.12 - ⇑ 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
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• 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 guideline-directed medical therapy
Final Conclusion
MitrClip is not currently approved for the treatment FMR in the U.S.
