Inter-‐Atrial Shunt Device

to Treat Heart Failure

Vivek Y. Reddy, MD

Helmsley Trust Professor of Medicine

Director, Cardiac Arrhythmia Service

The Mount Sinai Hospital

vivek.reddy@mountsinai.org

Disclosures

• Grant support and/or Consultant: – (DC Devices) Corvia Medical*

* I own stock options in this company

• I will be discussing unapproved and off-

label use of catheter devices

HFPEF: Prevalence increasing

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

Clinical Categories of HFpEF

1) “Garden-variety” HFpEF (HTN, DM, obesity, CKD)

2) CAD-HFpEF

3) Right heart failure-HFpEF

4) A-fib predominant HFpEF

5) HCM-like HFpEF

6) High-output HFpEF

7) Valvular HFpEF (multiple 2+ lesions)

8) Rare causes of HFpEF (“zebras”)

Oktay A, Shah SJ. Curr Cardiol Rev 2014

HFpEF Effect of Exercise on Hemodynamics

SJ.Shah. TCT Presentation (2015)

REST After 1 min of Exercise

HFpEF Physiology Mechanism of Action: Inter-Atrial Shunt Device

BA.Borlaug et al. Circ Heart Fail (2010)

LV Filling

Pressures ( LAP)

Pulmonary Venous

HTN ( PCWP)

Pulmonary Edema,

Dyspnea at Rest/Exercise

Hypothesis

Inter-Atrial Shunt Device Mechanism of Action

HFPEF Abnormal LV Relaxation

Elevated Left atrial Pressure Pulmonary Edema & Symptoms1 (Particularly During Exercise)

Transcatheter implant to create a small2 permanent interatrial shunt

• Shunt allows blood to move from the higher pressure LA to the lower pressure more compliant RA

• Reduces LA Pressure without compromising forward LV cardiac output and without causing RV overload

2 The 8 mm shunt results in Qp:Qs ratio (Pulmonary-to-Systemic flow ratio) 1.2-1.3

1 PCWP at rest is predictor of mortality (Dorfs, EHJ 2014)

Inter-Atrial Shunt Device (IASD) Computer Simulation

D.Kaye, S.Shah, D.Burkhoff J Card Fail (2014)

Inter-Atrial Shunt Device Proof of Concept Pilot Study (n=11)

L.Søndergaard, VY.Reddy D.Kaye et al, Eur J Heart Fail 16:796-801 (2014)

10

12

14

16

18

20

22

24

Baseline One Month*

Mechanistic Impact: PCWP change at rest

m-PCWP

RAPP-value = 0.005

P-value = NS

* Performed at 2, 3 months in 2 patients

Average PCWP decrease 5.5 mm Hg

Pilot Study 1 Year Outcomes

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

Hospitalizations

Ho

sp

ita

liza

tio

ns/Y

ea

r

Year Prior

Year Post

0

0.5

1

1.5

2

2.5

3

3.5

4

NYHA CLASS

NY

HA

CL

AS

S

Baseline

1 Year

280

290

300

310

320

330

340

350

360

6MWTD (M)

6 M

inu

te W

alk

Dis

tan

ce

Baseline

1 Year

0

10

20

30

40

50

60

MLWHF

ML

WH

F

Baseline

1 Year

p =0.030 p = 0.017 p = NS p = 0.057

Survival 11/11 100%

Freedom from HFH 9/11 82%

Improved QOL 8/9 89%

Survival, no HFH & worsening QOL 8/11 73%

Malek F / Neuzil P / Reddy V, Int J Cardiol 187:227 (2015)

IASD: CE Mark Clinical Trial Demographics (n=66)

S.Shah, TCT Presentation (2015)

• Symptomatic HF

• Preserved LVEF (> 40%)

• Elevated PCWP at rest or during exercise

IASD Clinical Trial Design Information to Consider

• Who should be studied? Inclusion/Exclusion? – Clinical predictors vs Hemodynamic criteria

• What should the endpoints be? – Composite Efficacy:

• CV Mortality

• HF Hospitalization

• (Anything Else?) – What options do patients currently have?

– Safety

IASD Clinical Trial Design Inclusion / Exclusion Considerations

• Preserved LVEF (>40%, >45%)

• History of Heart Failure – HF Hospitalization

– HF Symptoms

• Severity of HF – NYHA Class (II-IV vs III-IV)

– Recent/Frequent HF Hospitalizations

– Biomarkers: BNP

• Hemodynamic Parameters: – Elevated PCWP

– Not elevated RA / PVR

• Implication of Hemodynamic

Inclusion Criteria: Patients require

invasive procedure to qualify

• How many patients will not receive

the device? ~25-30% screen out

• Facilitates the possibility of a sham

procedure clinical trial design

IASD Clinical Trial Design Information to Consider

• Who should be studied? Inclusion/Exclusion? – Clinical predictors vs Hemodynamic criteria

• What should the endpoints be? – Composite Efficacy:

• CV Mortality

• HF Hospitalization

• (Anything Else?) – What options do patients currently have?

– Safety

IASD Clinical Trial Design What can TOPCAT teach us?

• 5% Alpha, 90% Power

• Control = 8.5% rate, IASD = 30% fewer events (5.95%)

• Total # of patients 4324 patients

IASD Clinical Trial Design What can TOPCAT teach us?

• 5% Alpha, 80% Power

• Control = 8.5% rate, IASD = 30% fewer events (5.95%)

• Total # of patients 3230 patients

IASD Clinical Trial Design Information to Consider

• Who should be studied? Inclusion/Exclusion? – Clinical predictors vs Hemodynamic criteria

• What should the endpoints be? – Composite Efficacy:

• CV Mortality

• HF Hospitalization

• (Anything Else?) – What options do patients currently have?

– Safety

HFpEF Treatments No Positive Trials!!

Is Lasix the only option that we

have to treat our HFpEF patients??

IASD: CE Mark Clinical Trial Efficacy at 1 Month

S.Shah, TCT Presentation (2015)

IASD Clinical Trial Design Primary Efficacy Endpoint

• Composite:

– CV Mortality

– HF Hospitalization

– Clinical Improvement: • Responder/Non-Responder designation

• Eg: QOL improvement on MLWHF or 6MWT

• [ Mandate a good control group = sham procedure ]

IASD Clinical Trial Design Information to Consider

• Who should be studied? Inclusion/Exclusion? – Clinical predictors vs Hemodynamic criteria

• What should the endpoints be? – Composite Efficacy:

• CV Mortality

• HF Hospitalization

• (Anything Else?) – What options do patients currently have?

– Safety

• Champion Trial (CardioMEMs)

• A sample size of 306 needed to

achieve 90% power and to detect

differences as small as 7% from

the null hypothesis rate of 80%

• Rem: CardioMEMs is a

diagnostic device vs IASD (which

is therapeutic device)

IASD: CE Mark Clinical Trial SAEs (n=66, within 30 days of procedure)

S.Shah, TCT Presentation (2015)

IASD: Clinical Trial Considerations Other Clinical Considerations

• Which type of HFpEF patients benefit most?

• Are there patients in whom CO will decrease?

• What are the long-term effects on the RV?

• After deployment, what happens in the setting of acute RV stress (e.g., acute PE)?

• Is there risk for RA dilation with progressive tricuspid regurgitation?

IASD Final Thoughts

• The character of heart failure is changing

• There are no effective therapies for HFpEF

• The IASD – (Probably) does not address underlying physiology

– A Novel Concept: • Reasonable safety in first-in-man experience

• Good reasons to consider that it will be effective

– FIM & CE Mark studies will follow pts to 3 years

– Received conditional approval to start a 40-pt randomized feasibility trial in the US