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Interatrial Shunt for the Treatment of Herat

Failure with Preserved Ejection Fraction

1

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

3

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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13

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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15

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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21

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

29

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)

32

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