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transcript
10/4/2019
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Interatrial Shunt for the Treatment of Herat
Failure with Preserved Ejection Fraction
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Rami Kahwash, MDProfessor in Internal Medicine
Division of Cardiovascular MedicineSection of Heart Failure/Transplant
The Ohio State UniversityWexner Medical Center
Objectives
Review the incidence and demographics of Heart Failure with preserved Ejection Fraction (HFpEF)
Understand the pathophysiology for HFpEF
Review management of HFpEF
Discuss the role of Left Atrial Pressure (LAP) in symptoms & prognosis of HFpEF
Highlight future directions for management of HFpEF including InterAtrial Shunt Device (IASD)
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Definition
HFpEF variably classified as EF >40%, >45%, >50%
Syndrome of HFpEF: clinical signs or symptoms of HF
evidence of preserved or normal LVEF
evidence of abnormal LV diastolic dysfunction by Doppler echocardiography or cardiac catheterization
More challenging to diagnose than HFrEF – largely diagnosis of exclusion
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Vasan RS, Levy D. Circulation 2000
DD vs. DHF vs. HFpEF
4Courtesy of Sanjiv J. Shah. MD
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A Simple, Evidence-Based Approach to Help Guide Diagnosis of Heart Failure With Preserved Ejection Fraction, Volume: 138, Issue: 9, Pages: 861-870, DOI: (10.1161/CIRCULATIONAHA.118.034646)
H2-FPEF Score for Diagnosis HFpEF: Increasing Prevalence
By 2020, 65% of hospitalized
HF pts will have EF > 40%
By 2020, 65% of hospitalized
HF pts will have EF > 40%
GWTG - HF: N=110,621 patients hospitalized with HF; P<0.0001 for trend of increased HFpEF prevalence (based
on data from Steinberg et al. Circulation 2012)
Oktay A, Shah SJ. Curr. Cardiol. Rev. 2013
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Heart Failure Outcomes
Owan TE et al, NEJM. 2006
5-yr mortality: HFpEF 65%, HFrEF 68%, (HR 0.96, p < 0.03)HFrEF: Survival increased over time (HR 0.98/yr, p = 0.005)
HFpEF: Survival did not change over time8 Borlaug BA, Redfield MM. Circulation
2011;123:2006-2014
HFpEF, Few Established Therapies
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Management – General Principles
Impaired response to stress Atrial fibrillation: loss of atrial
contraction reduces LV filling and stroke volume
Tachycardia: shortens duration of diastole
Elevated BP: increases ventricular wall stress worsening myocardial relaxation
Acute ischemia worsens diastolic function
All may result in ↑ LVEDP, pulmonary congestion, or edema
9 10 Yancy, et al. JACC 2013
HFpEF, Few Established Therapies
2017 Update: Class IIa recommendation for use of aldosterone antagonists in appropriately selected patients with HFpEF (with EF ≥45%, elevated BNP or HF admission within 1 year, estimated glomerular filtration rate >30 and creatinine <2.5 mg/dl, potassium <5.0 mEq /L), to decrease hospitalizations.
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Phenotype-Specific Treatment of Heart Failure With Preserved Ejection Fraction, Volume: 134, Issue: 1, Pages: 73-90, DOI: (10.1161/CIRCULATIONAHA.116.021884)
HFpEF, Pathophysiology
Phenotype-Specific Treatment of Heart Failure With Preserved Ejection Fraction, Volume: 134, Issue: 1, Pages: 73-90, DOI: (10.1161/CIRCULATIONAHA.116.021884)
HFpEF, Phenotype –Specific Treatment
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Pacing for HFpEF?
LV chamber size and compliance can be beneficially modulated by elevating heart rate for short periods of time
Normal to small cavity
Concentric Hypertrophy
HFpEF PhenotypeImproved exercise capacity
Improved LV filling Reduced stiffness and
fibrosis
Case Presentation78 Year-old woman referred for evaluation of progressive DOE
PMH: HTN, DM II
MEDs: Norvasc, HCTZ, metformin
ECG: NSR, LVH by voltage criteria, LAE
CXR and PFT: unremarkable
Lab: BNP~ 80
Stress Echo: exercised 3 minutes and stopped due to SOB & fatigue. No stress induced WMA at HR achieved.
Echo: mild LVH, normal LVEF, LAE, RVSP: 35 mm Hg
LHC: mild plaque disease, LVEDP: 14 mm Hg
RHC: RA: 5, PA: 34/13, PCWP: 14, CO/CI: 5/2
Next Step?
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Eur Heart J. 2015;36(38):2585-2594. doi:10.1093/eurheartj/ehv338
Amyloid Prevalence in HFpEF (13.3 %)
Borlaug et al. 2010; Circ Heart Fail 3:588-595.
Patients with exertional dyspnea, EF > 50%, n = 55
- No significant coronary disease- Normal brain natriuretic peptide, resting
hemodynamics - mPAP < 25 mm Hg; PCW < 15 mm Hg
- Exercise PCW > 25 occurred in 32/55- Greater increase in PCW- Tempered increases in HR, cardiac output- PASP > 45 mm Hg ~95% Sn and Sp
Heart Failure with Preserved Ejection Fraction
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Dorfs et al., European Heart Journal (2014) 35, 3103–
3112
Retrospective study, n = 355 with suspected HFpEF
Exercise PCW Pressure in HFpEF
Exercise Capacity
RestRest ExerciseExerciseRest Exercise
PCWP > 12PCWL > 25
Exercise Hemodynamics can identify HFpEF, correlate to exercise capacity, and are more predictive of mortality
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Sanjiv J. Shah JACC 2013;62:1339-1342
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ENVIRONMENT, DIETCOMORBIDITIES GENETIC SUSCEPTIBILITY
LA pressure
HFpEF
EXERCISE-INDUCED
DIASTOLIC DYSFUNCTI
ON
VOLUME OVERLOAD
PULMONARY HTN,
RV FAILURE
Three types of HFpEF presentation
Shah SJ. JACC 2013
HFpEF: A New Approach L → R Shunts may Reduce HF Symptoms
• Lutembachersyndrome described in 1916
• ASD in the context of mitral stenosis1-4
• MS patients with congenital ASD did better compared to MS w/o ASD
1 Firket,1880; 2 Lutembacher, 1916; 3 Rosenthal,1956; 4 Espino-Vela, 1959; 5 Aldridge, 1965.
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Left to Right Shunts and Heart Failure
Ewert et al., 2001, CCI 52:177-80
Masked Left Ventricular Restriction in Elderly Patients with Atrial Septal Defe
18 patients had LA pressures measured during balloon occlusion
In 7, LA pressure increased considerablyTwo of them proceeded with ASD closure and
developed CHF
CAUTION Investigational device. Limited by Federal (or United States) law to investigational use
InterAtrial Shunt Device - Mode of Action
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Elevated LV fillingpressures
(Elevated LAP)
Pulmonary Venous hypertension
Pulmonary Congestion &
Dyspnea (rest/exercise)
Transcatheter interatrial shunt device
IASD area of
intervention
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Computer simulation demonstrated that an 8mm interatrial shunt device
(IASD®) would provide acute LA decompression during exercise
Left Atrial Decompression: IASD Rationale
LA pressureRA pressure
Kaye et al J Card Fail 2014
Dr. Scott Lilly
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“One person with passion is better than forty people merely interested”.
~ E.M Forster
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Feldman T et al., CircHeart Fail 2016
LA legs deployed
Post-Deployment
LA
RA
Corvia Interatrial Shunt Device (IASD)
Implant19mm
OD 8 mm ASD
Catheter (16 Fr)
Corvia Medical IASD®
Clinical Studies• Pilot study (N=11): non-randomized, single-arm
⁃ Completed (Søndergaard L, et al. Eur J Heart Fail 2014)
• REDUCE LAP-HF (CE Mark) Study (N=64): non-randomized, single-arm⁃ Completed (Hasenfuß Lancet 2016; Kaye Circ. HF 2016 )
• REDUCE LAP-HF I (N=44): RCT mechanistic study⁃ FDA IDE 30 Day Complete (Feldman T… Shah SJ. Circulation.
2018;137:364–375)⁃ 1Y follow-up complete
• REDUCE LAP-HF II (N=608): RCT pivotal study⁃ FDA approved IDE; recruiting
• HFrEF Feasibility study⁃ FDA approved IDE; recruiting
• REDUCE LAP-HF III (N=100): Post-market Registry Germany⁃ Recruiting
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Hasenfuß G: Lancet 2016; 387: 1298–304
CE-Mark
PCW increased from 17 35 mm Hg with exercise
Inclusion• N = 64, LVEF ≥ 40% • NYHA class II-IV • PCWP ≥ 15 mmHg
(rest), ≥ 25 (exercise)
1-year survival 95%; No device related adverse events
CE-Mark
Kaye Circ Heart Fail. 2016 Dec;9(12)
Shunt Fraction (Qp:Qs)
1.27
1.25
0
0.5
1
1.5
2
Baseline 6M 12M0
5
10
15
min
utes
Exercise time
* *
Baseline 6M 12M0
20
40
mm
Hg
PCWPBaseline 6M 12M
020406080
Wat
ts
Workload
** **
Baseline 6M 12M0
5
10
15
L/m
in
Cardiac Output
***
Baseline 6M 12M0
50
100
150
mm
Hg/
(W/k
g)
Work indexedPCWP
* **
Baseline 6M 12M0
50
100
%
NYHA Class
IIIIIIIV
*** ***
Baseline 6M 12M
200
300
400
500
met
res
6MWD
** **
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Safety (MACCE) and Device Performance
MACCE event
Six months %
One year %
Death 0 4.7 (3/64)
Stroke 0 1.5 (1/64)* (ptdied)
MI 0 0
Systemic embolic event
0 0
Implant removal
0 0
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Device patency confirmed in 54 subjects (by echo or oximetry)
Safety (MACCE) and Device Performance
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Effectiveness
Six months %
One year %
L R Shunt flow (Echo) 100 (49/49) 100 (48/48)
R L Shunt flow (Echo) 0 0
Qp:Qs 1.27 ± 0.24 1.28 ± 0.25
Device patency confirmed in 54 subjects (by echo or oximetry)
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Efficacy at 6 & 12 months(Patients with data at all 3 time points)
0
10
20
30
40
50
60
MLW
HF
p < 0.0001
N=59
p < 0.0001
MLWHF
310
320
330
340
350
360
370
6 Min W
alking
Distance (m
)
p = 0.0013
p = 0.007
N=55
6MWTD
1
1.5
2
2.5
3
NYH
A Class
p < 0.0001
p < 0.0001
N=59
NYHA
CONFIDENTIAL
Mean at 1 year: 15 points82% improved > 5 point
Mean at 1 year: 33m47% improved > 20m
Mean at 1 year: -0.871%* improved I-II classes
* Higher than at 6M: p =0.04
Invasive Hemodynamic Results (rest)
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Patients with data at all 3 time points.
Baseline
Six mont
hs
One year
RA pressure
8 ± 3 11 ± 6 10 ± 4
PA meanpressure
25 ± 8 23 ± 7 26 ± 8
Wedge pressure
19 ± 6 16 ± 8 17 ± 6
Cardiacoutput
5.2 ± 1.3 6.3 ±1.4**
6.7 ±1.8**
** p<0.01 vs baseline
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Corvia Medical IASD®
Clinical Studies• Pilot study (N=11): non-randomized, single-arm
⁃ Completed (Søndergaard L, et al. Eur J Heart Fail 2014)
• REDUCE LAP-HF (CE Mark) Study (N=64): non-randomized, single-arm⁃ Completed (Hasenfuß Lancet 2016; Kaye Circ. HF 2016 )
• REDUCE LAP-HF I (N=44): RCT mechanistic study⁃ FDA IDE 30 Day Complete (Feldman T, Shah SJ. Circulation.
2018;137:364–375)⁃ 1Y follow-up complete, submitted ESC
• REDUCE LAP-HF II (N=608): RCT pivotal study⁃ FDA approved IDE; recruiting
• HFrEF Feasibility study⁃ FDA approved IDE; recruiting
• REDUCE LAP-HF III (N=100): Post-market Registry Germany⁃ Recruiting
REDUCE LAP-HF I (n=44)Randomized, controlled trial (1:1)
NYHA III-IV, LVEF > 40%, HF Hosp or ↑BNPPCW > 25 mm Hg (Exercise); PCW - RA > 5 mm Hg
IASDCONTROL
30-d Hemodynamic Outcomes
*No adverse events at 30-d follow up in treated armFeldman et al., 2018 Circulation
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010
20
30
IASD Change in NYHA
Improved II ClassesImproved I ClassNo ChangeDeclined 1No dataDead
05
10152025
Control Change in NYHA
Improved II ClassesImproved I ClassNo ChangeDeclined 1No DataDead
At 12 months, there was a trend toward greater improvement in NYHA class compared to Control:• More patients improved 2 classes• More patients improved 1 class• Fewer patients with an increase in NYHA class• Greater reduction in median and mean NYHA class from baseline to 12
months
Feldman, EuroPCR, May 2018
REDUCE LAP HF I: 12M Efficacy
Key Secondary Outcome Measures at 12 Months*
4.54.8
0
2
4
Perc
ent
Cardiovascular Death
0.22
0.63
0
0.25
0.5
0.75
1
Rat
e Pe
r Pat
ient
Yea
r
HF Hosp/Visits w IV
diuresis
P=0.064
16
13.6
0
5
10
15
20
Cha
nge
in D
ista
nce
6 Min Walk
10.5
8.1
0
5
10
15
Cha
nge
in Q
OL
KCCQ
N=39*powered for primary and not for secondary outcome measures
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Change in NYHA Functional Class: InterAtrial Shunt Device vs. Sham
ControlIASD
Control
Cumulative Incidence of MACCRE and Heart Failure Events Requiring Intravenous Diuretic Treatment Through 12 Months
MACCRE Heart Failure Events
ControlIASD
ControlIASD
Time after Randomization (days)
Cum
ulat
ive
Inci
denc
e of
H
eart
Fai
lure
Eve
nt
Req
uirin
g IV
Tre
atm
ent
Cum
ulat
ive
Inci
denc
e of
Maj
or
Adve
rse
Car
diac
C
ereb
rova
scul
ar a
nd R
enal
Ev
ents
(MAC
CR
E)
0 30 90 180 270 365
Time after Randomization (days)0 30 90 180 270 365
log-rank p=0.20
log-rank p=0.08
MACCRE: Death, stroke, device/procedure related adverse events, renal dys
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Baseline, 6-, and 12-Month Echocardiographic Parameters of Cardiac Structure and Function• No significant change in
left heart structure/function
Trend towards greater reduction in LA volume index in IASD vs. control at 12 months (6.3±10.7 vs. 1.5±14.2 ml/m2; p=0.078).
Increase in RVEDV (p=0.01) without any change in RVEF in the IASD arm.
Conclusions
HF hospitalization NYHA class
REDUCE LAP-HF I confirms the 1 year patency of the IASD
.
Through 1 year of follow-up IASD treatment compared to sham-control: Appears safe Is associated with favorable
trends in MACCRE HF hospitalization NYHA class
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Available at jama.com and on The JAMA Network Reader at mobile.jamanetwork.com
.
One-Year Safety and Clinical Outcomes of a Transcatheter Interatrial Shunt Device for the Treatment of Heart Failure With Preserved Ejection Fraction in the Reduce Elevated Left Atrial Pressure in Patients With Heart Failure (REDUCE LAP-HF I) Trial: A Randomized Clinical Trial.
Published online August 27, 2018Available at jama.com and on The JAMA Network Reader at mobile.jamanetwork.com
Primary endpoint composite of:• Cardiovascular mortality or non‐fatal, ischemic stroke through 12
months; and• Rate of total (first plus recurrent) HF admissions, healthcare
facility visits for IV diuresis for HF through 12 months; and• Change in KCCQ score between baseline and 12 months.
Major secondary efficacy endpoints • Change in NHYA class between baseline and 12 months• Change in KCCQ score between baseline and 12 months
The Primary endpoint will be analyzed using the Finkelstein‐Schoenfeld methodology
REDUCE LAP‐HF II StudyN = 608
REDUCE LAP-HF II StudyMulticenter, Prospective, 1:1 Randomized, SHAM Controlled, DOUBLE Blinded Trial
Treatment Groupn = 304
Corvia IASD Implant
Control Groupn = 304
Non Implant
ClinicalTrials.gov Identifier: NCT03088033
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WT Abraham, TCT 2017
Porcine pericardial leaflets– improves flow
mechanics– prevents R to L
shunting and paradoxical embolization
Hourglass shape– secure and atraumatic septal
retention– minimal ID 5.1 mm orifice
ePTFE encapsulation– blocks tissue ingrowth
Right Atrium
Left Atrium
The V-Wave Shunt Device
Nitinol frame
Inter-atrial septum
• Anticoagulation for 3 months
14F delivery system
Eigler N et al. Structural Heart 2017;1:40-8
N=21 sheep14 V-Wave 5.1 mm
shunts
7 Controls
Improved
• Hemodynamic
s
• LV function
• Survival (93%
v 57%)
QpQs 1.2:1
Pre-ClinicalCardiac Unloading with an Implantable Interatrial Shunt in Heart Failure: Serial Observations in an Ovine Model of Ischemic CardiomyopathyNeal L. Eigler, Carlos L. del Rio, Stefan Verheye, Patrick I. McConnell, Scott M. Lilly, Robert George, Robert L. Hamlin, Yukie Ueyama, Bradley L. Youngblood, Sergio Shkurovich, Gad Keren & William T. Abraham
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II. Devices and Outcomes
45Amat-Santos et al., 2015 EuroIntervention 10(9): 1127-1131
Del-Trigo et al, 2016 Lancet (387):1290-97
10 patients with HFrEF, NYHA 3, Mean LVEF 25%100% successfully implanted
9/10 survived to 3 months
6-min Walk
Feasibility
Mean PA PressureRA Pressure PCWP (Rest)
23 17 mm Hg
244 319 m
No Change Resting RA, mPA Pressure
II. Devices and Outcomes
• Reduced L R shunt flow• Absent in 5/26 (15%)• Reduced in 13/36 (36%)
• Neointimal proliferation • Thickening, commissural fusion,
fixation and stenosis
• Not associated with thromboembolic events
Implant Follow Up
GW Stone, TCT 2017
V-Wave Open-LabelN = 38, 30 HFrEF, 8 HFpEF, 12-mo
Follow upFeasibility
V-Wave
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P=0.009 vs. baseline
P=0.003 vs.baseline P=0.10 vs.
baseline
GW Stone, TCT 2017
V-Wave Open-LabelN = 38, 30 HFrEF, 8 HFpEF, 12-mo
Follow up
WT Abraham, TCT 2017
“Exit Hood” to block potential paradoxical
emboli
Hourglass shape– secure and atraumatic septal
retention– minimal ID 5.1 mm orifice
Full ePTFE encapsulation– blocks tissue
ingrowth
Right Atrium
Left Atrium
Generation 2: V-Wave Interatrial Shunt
Nitinol frame
Inter-atrial septum
DAPT for 6 months
14F delivery system
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Reducing Lung Congestion Symptoms Using the V-wave Shunt in Advanced
Heart Failure (RELIEVE-HF)
• Estimated enrollment 500 patients
• Inclusion: NYHA > III, HFrEF and HFpEF on GDMT, a HF
hospitalization in 12 months, or BNP > 300.
• Exclusion: PASP > 70, RV dysfunction, moderate or greater
valve disease
• Randomized 1:1
• Primary Outcomes
1. (Safety) Device related adverse events, cardiovascular
and neurological
2. (Effectiveness) Composite death, transplant or LVAD,
heart failure hospitalizations, and change in 6 minute walk test.
Enrolling now, estimated completion October 2021
Devices that permit interatrial flow are emerging for a range of conditions
Early experience suggests improved hemodynamics and functional status
Ongoing trials and surveillance Durability of functional improvement, shunt Potential side effects
Represent first device based therapies for HFpEF
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Conclusions
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THANK YOU