Updates: Trials of Transcatheter Mitral Valve Intervention SCRIPPS CLINIC Intervention Matthew J. Price MD Director, Cardiac Catheterization Laboratory, Scripps Clinic La Jolla, CA, USA Email: [email protected] Office: 858-824-5269
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Updates: Trials of Transcatheter Mitral ValveIntervention
SCRIPPS CLINIC
Intervention
Matthew J. Price MDDirector, Cardiac Catheterization Laboratory, Scripps ClinicLa Jolla, CA, USAEmail: [email protected]: 858-824-5269
TYPES OF MITRAL REGURGITATION
PRIMARY(DEGENERATIVE)
MITRAL REGURGITATION
SECONDARY(FUNCTIONAL)
SCRIPPS CLINIC
TYPES OF MITRAL REGURGITATION
PRIMARY(DEGENERATIVE)
MITRAL REGURGITATION
SECONDARY(FUNCTIONAL)
SCRIPPS CLINIC
IncreasingM itral
R egurgitation
IncreaseDilationof 1 year
P<0.001
No/mild SMR
1.0
0.8
Prospective study: 576 pts with HFrEF21% severe FMR, 32% mod FMR
SEVERE SECONDARY MR IS ANINDEPENDENT PREDICTOR OF MORTALITY2
Secondary MR is a Predictor of Mortality
SCRIPPS CLINIC
IncreaseL oad/S tress
M uscleDam age/L oss
DysfunctionofL eft
Ventricle
DilationofL eftVentricle
1 yearm ortality
upto
57% 1
No/mild SMR
Su
rviv
al
Moderate SMR
Severe SMR
Years
0.6
0.4
0.2
0 2 4 6 8
1. CioffiG,etal.EuropeanJournalofHeartFailure2005Dec;7(7):1112-7.2. GoliaschG etal.EHJ2018;39:39-46.Graphcourtesy ofDr.G S tone.
THE EDGE-TO-EDGE TECHNIQUE FOR SURGICAL MITRAL VALVE REPAIR
SCRIPPS CLINICOttavioOttavio Alfieri, MDAlfieri, MD
SCRIPPS CLINIC
Key Inclusion Criteria1. Ischemic or non-ischemic cardiomyopathy with LVEF 20%-50% andLVESD ≤70 mm
2. Moderate-to-severe (3+) or severe (4+) secondary MR confirmed by anindependent echo core laboratory prior to enrollment (US ASE criteria)
3. NYHA functional class II-IVa (ambulatory) despite a stable maximally-
SCRIPPS CLINIC
3. NYHA functional class II-IVa (ambulatory) despite a stable maximally-tolerated GDMT regimen and CRT (if appropriate) per societal guidelines
4. Pt has had at least one HF hospitalization within 12 months and/or aBNP ≤300 pg/ml* or a NT-proBNP ≤1500 pg/ml*
5. Not appropriate for mitral valve surgery by local heart team assessment
6. IC believes secondary MR can be successfully treated by the MitraClip
Adjusted by a 4% reduction in the BNP or NT-proBNP cutoff for every increase of 1 kg/m2 in BMI >20 kg/m2
Baseline Characteristics (i)
SCRIPPS CLINIC
Baseline Characteristics (ii)
HF parametersMitraClip +
GDMT (N=302)GDMT alone
(N=312)Echo core lab
MitraClip +GDMT (N=302)
GDMT alone(N=312)
Etiology of HF MR severity
- Ischemic 60.9% 60.6% - Mod-to-sev (3+) 49.0% 55.3%
- Non-ischemic 39.1% 39.4% - Severe (4+) 51.0% 44.7%
NYHA class EROA, cm2 0.41 ± 0.15 0.40 ± 0.15
SCRIPPS CLINIC
- I 0.3% 0% LVESD, cm 5.3 ± 0.9 5.3 ± 0.9
- II 42.7% 35.4% LVEDD, cm 6.2 ± 0.7 6.2 ± 0.8
- III 51.0% 54.0% LVESV, mL 135.5 ± 56.1 134.3 ± 60.3
- IV 6.0% 10.6% LVEDV, mL 194.4 ± 69.2 191.0 ± 72.9
HF hosp w/i 1 year 58.3% 56.1% LVEF, % 31.3 ± 9.1 31.3 ± 9.6
Prior CRT 38.1% 34.9% - 40% 82.2% 82.0%
Prior defibrillator 30.1% 32.4% RVSP, mmHg 44.0 ± 13.4 44.6 ± 14.0
Medication Use at Baseline
Maximally-tolerated dosesMitraClip + GDMT
(n=302)GDMT alone
(n=312)
Beta-blocker 91.1% 89.7%
ACEI, ARB or ARNI 71.5% 62.8%
Mineralocorticoid receptor antagonist 50.7% 49.7%
Nitrates 6.3% 8.0%
SCRIPPS CLINIC
Nitrates 6.3% 8.0%
Hydralazine 16.6% 17.6%
Diuretic 89.4% 88.8%
Chronic oral anticoagulant 46.4% 40.1%
Aspirin 57.6% 64.7%
P2Y12 receptor inhibitor 25.2% 22.8%
Statin 62.6% 60.6%
Primary Effectiveness EndpointHospitalizations for HF within 24 months
Annualized rates of HF hospitalization*
67.9%GDMT
283/416.8 pt-yrs
NNT (24 mo) = 3.1 [95% CI 1.9, 8.2]
SCRIPPS CLINIC*Joint frailty model
35.8%
67.9%
0% 10% 20% 30% 40% 50% 60% 70% 80%
alone
MitraClip+ GDMT
HR (95% UCL] =
0.53 [0.66]
P<0.001160/446.5 pt-yrs
283/416.8 pt-yrs
All-cause MortalityM
ort
alit
y(%
)
60%
80%
100%
46.1%
HR [95% CI] =
0.62 [0.46-0.82]
P<0.001
MitraClip + GDMT
GDMT alone
NNT (24 mo) =5.9 [95% CI 3.9, 11.7]
SCRIPPS CLINIC
All-
cau
se
0%
20%
40%
Time After Randomization (Months)0 3 6 9 12 15 18 21 24
46.1%
29.1%
MitraClip + GDMT
GDMT alone
302 286 269 253 236 191 178 161 124
312 294 271 245 219 176 145 121 88
No. at Risk:
5.9 [95% CI 3.9, 11.7]
Powered Secondary Endpoints- Tested in hierarchical order1 -
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
SCRIPPS CLINIC1All powered for superiority unless otherwise noted; 2Powered for noninferiority of the device
vs. the control group; 3Powered for noninferiority against an objective performance goal
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
Primary Safety EndpointFreedom from Device-related Complications within 12 months
MitraClip procedure attempted N=293
Device-related complications 9 (3.4%)
- Single leaflet device attachment 2 (0.7%)
- Device embolization 1 (0.3%)80%
90%
100% 96.6%*
88% OPC
94.8% [95% LCL]
P<0.001
SCRIPPS CLINIC
- Endocarditis requiring surgery 0 (0.0%)
- Mitral stenosis requiring surgery 0 (0.0%)
- Left ventricular assist device implant 3 (1.2%)
- Heart transplant 2 (0.8%)
- Any device-related complicationrequiring non-elective CV surgery
1 (0.3%)
*KM estimate; **Calculated from Z test with Greenwood’s method of estimatedvariance against a pre-specified objective performance goal of 88%
50%
60%
70%
80% P<0.001
MitraClip Crossovers in GDMT-Assigned Patients
GDMT alone(N=312)
MitraClip crossoverbefore 24 months
(N=5)*
No MitraClip crossoverbefore 24 months
(N=138)Not eligible forcrossover at 24
SCRIPPS CLINIC
(N=5)*(N=138)crossover at 24months (N=169)
Death: 124LVAD: 16Transplant: 9Withdrawals: 26Lost to follow up: 3Other†: 2
MitraClip crossoverbetween 24 and 36 mos
(N=53/138; 38.4%)
No MitraClipcrossover
(N=85)
Total Crossover(N=58/312; 18.6%)
Duration from randomization to crossover:Median: 25.5 months; Range: 0.2 to 32.9 months
Follow-up after crossover:Median: 7.7 months; Range: 0.0 to 43.6 months
†No FU data post 24 monthsPt may be in more than one category
*Protocol deviation
200
300
400
mu
lati
ve
ali
zati
on
s(n
) MitraClip + GDMT
GDMT alone 299in 158 pts
Primary Effectiveness EndpointAll Hospitalizations for HF within 36 months
All patients, ITT, including crossovers
HR [95% CI]# =
0.51 [0.39, 0.67]
P=0.000001
SCRIPPS CLINIC
# at Risk:
MitraClip + GDMT 302 269 238 219 189
GDMT alone 312 272 223 185 144
0
100
0 6 12 18 24 30 36
Cu
mH
FH
osp
ita
Time after randomization (months)
169in 95 pts
#Joint frailty model
NNT = 3.2 [95% CI 2.5, 4.5]
200
300
400
mu
lati
ve
ali
za
tio
ns
(n) MitraClip + GDMT
GDMT alone
378in 196 pts
220in 114 pts
Primary Effectiveness EndpointAll Hospitalizations for HF within 36 months
All patients, ITT, including crossovers
299in 158 pts
SCRIPPS CLINIC
# at Risk:
MitraClip + GDMT 302 269 238 219 189 128 93
GDMT alone 312 272 223 185 144 89 68
0
100
0 6 12 18 24 30 36
Cu
mH
FH
os
pit
a
Time after randomization (months)
HR [95% CI]# = 0.49 [0.37, 0.63]
P=0.00000006
NNT = 3.0 [95% CI 2.4, 4.0]
#Joint frailty model
169in 95 pts
NNT = 3.2 [95% CI 2.5, 4.5]
40%
60%
80%
100%
pit
ali
zati
on
(%)
First Heart Failure HospitalizationAll patients, ITT, including crossovers
56.4%
MitraClip + GDMT
GDMT alone
HR [95% CI] =
0.51 [0.39, 0.66]
P=0.0000001
SCRIPPS CLINIC
0%
20%
40%
0 6 12 18 24 30 36
HF
Ho
sp
Time after randomization (months)
34.8%
Event rates are Kaplan-Meier time-to-first event estimates
# at Risk:
MitraClip + GDMT 302 238 196 176 148
GDMT alone 312 206 156 120 87
NNT = 4.6 [95% CI 3.3, 7.5]
40%
60%
80%
100%
pit
ali
za
tio
n(%
)First Heart Failure Hospitalization
All patients, ITT, including crossovers
81.5%
46.5%56.4%
MitraClip + GDMT
GDMT alone
SCRIPPS CLINIC
0%
20%
40%
0 6 12 18 24 30 36
HF
Ho
sp
Time after randomization (months)
34.8%
Event rates are Kaplan-Meier time-to-first event estimates
# at Risk:
MitraClip + GDMT 302 238 196 176 148 101 66
GDMT alone 312 206 156 120 87 37 20
HR [95% CI] = 0.43 [0.34, 0.54]
P=0.00000000000004
NNT = 2.9 [95% CI 2.3 3.8]NNT = 4.6 [95% CI 3.3, 7.5]
40%
60%
80%
100%
tyo
rH
FH
(%)
All-Cause Mortality or HF HospitalizationGDMT pts censored at time of crossover; Crossovers landmarked at MitraClip procedure
87.0%
58.8%66.8%
44.5%
MitraClip + GDMT
GDMT alone, crossovers censored
GDMT, crossovers to MitraClip
SCRIPPS CLINIC
0%
20%
40%
0 6 12 18 24 30 36
Mo
rta
lit
Time after randomization (months)
44.5%
28.0%
For crossover patients, follow-up duration is from the crossover procedure date; events at procedure dates are excluded.Event rates are Kaplan-Meier time-to-first event estimates, with landmark analysis for crossover patients
# at Risk:MitraClip + GDMT 302 238 196 176 148 101 66
GDMT only, crossovers censored 312 205 155 119 85 33 19
GDMT crossovers to MitraClip 58 30 22
200
250
300
350
S CR IP P S M EM O R IAL HO S P IT AL L A JO L L A-27616*S HAR P M EM O R IAL HO S P IT AL -27008
S T JO S EP H HO S P IT AL -27638
L O M A L IN DA M ER CAN T IL E-36526
TRANSCATHETER MITRAL VALVE REPAIR:SITE VOLUMES ACROSS THE GREATER SAN DIEGO AREA
pro
ce
du
res
SCRIPPS LJ
SHARP
SCRIPPS CLINIC
0
50
100
150
200
P rocedures
HO AG M EM O R IAL HO S P P R ES BYT ER IAN -30673U N IVER S IT Y O FCA S AN DIEGO M ED CT R -27179S T BER N AR DIN EM EDICAL CEN T ER -28370
EIS EN HO W ER M EDICAL CEN T ER -28962
KAIS ER FO U N DAT IO N HO S P IT AL -38997
Site
#o
fm
itra
clip
pro
ce
du
res
SHARP
UCSDHOAGL.LINDA
ST JOE’S
ST B’S EISENHOWER
Procedural Success: Learning Curve Analysis*
Acceptable (≤ 2+ residual MR) Optimal (≤ 1+ residual MR)
92% 93% 95% 65% 73% 80%
SCRIPPS CLINIC*Curves generated using hierarchical generalized linear mixed models
Procedure Time Procedural Complications
Procedure Time and Procedural Complications*
SCRIPPS CLINIC* Curves generated using hierarchical generalized linear mixed models
Procedure Time Procedural Complications
Procedure Time and Procedural Complications*
SCRIPPS CLINIC* Curves generated using hierarchical generalized linear mixed models
MORTALITY BENEFIT FOR HEART FAILURE THERAPIES
SCRIPPS CLINIC
CourtesyJoann Lindenfeld
Edwards PASCAL Transcatheter Valve Repair System
Central spacer intended to fill theregurgitant orifice area
Implant
Spacer
CAUTION: Investigational device. Limited by Federal (or United States) law to investigational use.
Spacer and broad, contoured paddle designreduce stress on leaflets
Clasps allow for independent leafletcapture and the ability to fine-tuneleaflet position
Paddles
The CLASP IID Cohort Design
Patients will be randomized 2:1 toeither treatment with the EdwardsPASCAL System (Device Group) orMitraClip System (Control Group).MitraClip System (Control Group).
Transcatheter Tricuspid Valve Edge-to-Edge Repair
SCRIPPS CLINIC
TRILUMINATE Pivotal Study Design
• Prospective, randomized, controlled, multi-center trial
• 450 subjects enrolled at up to 80 sites in the US, Canada, Europe
• Primary endpoint to be assessed after 350 subjects reach 12 month follow-up
• Adaptive design incorporated, in case study is under-powered to show a difference
TRIALDESIGN
• To evaluate the safety and effectiveness of the TriClip device in improving clinical outcomes in symptomaticpatients with severe tricuspid regurgitation (TR) who have been determined by the site’s local heart team to be
SCIENTI-FIC
CAU T IO N :Investigationaldevice.L im ited by federal(U .S .)law toinvestigationaluseonly.N otavailableforsale.© 2019 Abbott.Allrightsreserved.S E2945492 R ev.A 29
Randomized Arm
A composite of mortality 0r tricuspid valve surgery, heart failure hospitalizations, and quality of lifeimprovement assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ), evaluated at 12 months ina hierarchical fashion using the Finkelstein-Schoenfeld methodology
Single Arm:
Survival and quality of life improvement (assessed using KCCQ) at 12 months compared to baseline. In thiscohort of sick patients in which it is believed TR cannot be reduced to moderate or less, it is expected that therewill be significant improvement in quality of life at 12 months post enrollment
PRIMARYENDPOINT
patients with severe tricuspid regurgitation (TR) who have been determined by the site’s local heart team to beat intermediate or greater estimated risk for mortality with tricuspid valve surgery
FICOBJECTIVE
Medtronic Intrepid TMVR
SCRIPPS CLINIC
APOLLO TMVR TRIAL
• Patients with symptomaticmoderate-to-severe or severemitral regurgitation
• Self-expanding valve, nitinolstent and bovine pericardiumleaflets
SCRIPPS CLINIC
leaflets
• Hybrid procedure with CTsurgeon and InterventionalCardiologist
• 35Fr delivery catheter
• Trans-apical access
INTREPID TMVR DEPLOYMENT
SCRIPPS CLINICLBL-0044 Rev A Confidential
INTREPID GLOBAL FEASIBILITY STUDY: PRIMARY ANDSECONDARY OUTCOMES
SCRIPPS CLINIC
INTREPID GLOBAL FEASIBILITY STUDY: MITRALREGURGITATION OUTCOMES
SCRIPPS CLINIC
INTREPID GLOBAL FEASIBILITY STUDY: CHANGE IN NYHACLASS
SCRIPPS CLINIC
APOLLO TMVR - THE SCRIPPS EXPERIENCE
• 3 implants performed to date
• Enrollment challenges: anatomyexcludes many patients
• Risk of LVOT obstruction
SCRIPPS CLINIC
• Annular dimensions• Severe annular calcification• Severe RV dysfunction
N = 23 patients
INTREPID TMVR: CT AT 1 MONTH FOLLOW-UP IN FIRST PATIENT TREATEDAT SCRIPPS
SCRIPPS CLINIC
APOLLO TMVR TRIAL STATUS
• 750+ patients consented
• 190+ patients enrolled
• 55 US Sites participating
SCRIPPS CLINIC
• For “roll-in” patients 30 day mortality after TMVR = 2% (n=51)
UPCOMING APOLLO TRIAL DEVELOPMENTS (I)
• Change from trans-apicalaccess to trans-femoral access
• Goal to decrease deliverycatheter size from 35Fr to 29Fr
SCRIPPS CLINIC
catheter size from 35Fr to 29Fr
• New valve iterationrecoverable until final release
• Expansion of trial to sites inEurope and Japan
UPCOMING APOLLO TRIAL DEVELOPMENTS (II)
SCRIPPS CLINIC
SAPIEN M3: Pursuing Safe & Effective TransfemoralValve Replacement to Eliminate Mitral RegurgitationU.S. Pivotal Trial
Innovation Evidence
In 15 patient EFS early clinicalContinued Early
Low-profile, Transfemoral
2019
SCRIPPS CLINIC
Modified SAPIEN 3 29mmvalve leverages proven design
Docking system facilitatesvalve anchoring;Retrievability allows foroptimal device placement
High technical success,93% reduction of MR to0 or 1+; no deaths fromany cause at 30 days1
Plan to initiate U.S.Pivotal Trial in late 2019
In 15 patient EFS early clinicalexperience:
Experience in 30+ patients
Continued EarlyFeasibility StudiesLow-profile, Transfemoral
easy-to-use delivery system
• COAPT: Overwhelmingly favorable results for MitraClip infunctional (secondary) MR, now with FDA indication
• Other edge-to-edge repair technologies:
• CLASP II: Noninferiority RCT of PASCAL vs. MitraClip
CURRENT STATE OF TMVR/TMV REPAIR TRIALS
SCRIPPS CLINIC
• CLASP II: Noninferiority RCT of PASCAL vs. MitraClip
• TMVR (replacement):
• APOLLO
• Transseptal technologies around the corner
• Challenges – anatomical eligibility
THE MITRAL VALVE IS GETTING POPULAR!
SCRIPPS CLINIC
Related Documents
