Interventional Intrusions into a “Medical” Condition:

Device Approaches to HFpEF

Nicholas J. Ruggiero II, MD, FACP, FACC, FSCAI, FSVM, FCPP Director, Structural Heart Disease and Non-Coronary Interventions

Director, JHI Vascular Laboratory Associate Director, Fellowship in Cardiovascular Diseases

Associate Professor of Medicine Sidney Kimmel Medical College

Disclosures

• Edward Lifesciences Consultant • Abbott Laboratories Consultant

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Importance of Elevated Left Atrial Pressure in HFpEF

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Wolsk E, Gustafsson F. EJHF 2017

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Exercise Capacity Survival

Follow-up (years)

Surv

ival

(%)

Dorfs S, et al. EurHeart J 2014

Work-corrected PCWP <25.5 mmHg/W/kg

Work-corrected PCWP >25.5 mmHg/W/kg P=0.03

ASD in the Setting of Mitral Stenosis

• Lutembacher Syndrome • Allows for decompression

of the left atrium • Large Reservoir:

• Right atrium • Great veins • Hepatic veins

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Scherlis and Cowley Ann Intern Med 1955 4

Interatrial Shunt Device

1/15/2020 Feldman T, Shah SJ. Circ Heart Fail 2016

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IASD proposed mode of action: dynamic decompression of overloaded LA chamber by shunting blood from LA RA

Corvia Investigational System

1/15/2020 Sanjiv J. Shah, MD, FAHA, FACC, FASE 6

Implant 19 mm OD 8 mm ASD

IASD Deployment

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• Flouroscopic + TEE/ICE Guidance • Venous Access 16 F • Standard Transeptal Access Mid Fossa

LA legs deployed Device Deployed

8 mm Diameter: Optimal Size For IASD

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Kaye D…Burkhoff D. J Card Fail 2014

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• Simulation using exercise hemodynamic data from HFpEF Patients

Corvia IASD Development Pipeline

1/15/2020 Sanjiv J. Shah, MD, FAHA, FACC, FASE

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Results of the IASD open-label Study (n=64)

• Inclusion Criteria: • Open Label • EF > 40% • NYHA II-IV • Elevated PCWP

• >15 mm Hg at rest • >25 mm Hg (supine exercise bike)

• Acceptable safety profile at 12, 24 months

1/15/2020 Hasenful G, Kaye D. Lancet 2016 Kaye D, et al. Circ Heart Fail 2016 10

*p<0.05, **p<0.01 vs. baseline

Results of the IASD open-label Study (n=64)

1/15/2020 Kaye D, et al. ESC Heart Fail 2018 11

Change In PCWP: Baseline to 1 Month

1/15/2020 Sanjiv J. Shah, MD, FAHA, FACC, FASE

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Patient Randomized to IASD Resting PCWP (mm Hg) Peak exercise PCWP (mm Hg)

1/15/2020 Sanjiv J. Shah, MD, FAHA, FACC, FASE

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Reduce LAP-HF I RCT: 1 Year Outcome

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Optimal Patient Selection 66 year old female with HFpEF

Who would benefit?

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Durability of Procedure

• 100% IASD patency rate at 1 year with left to right flow. • No device related thrombus • No evidence of failure • No need for retrieval

1/15/2020 Shah SJ, et al. JAMA Cardiol 2018

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Stroke Risk

• Open-label study, no risk of stroke out to 4 years.

• All patients receive asa 81 mg indefinitely.

• If not on anticoagulation then clopidogrel for 6 months.

• If on anticoagulation (DOAC, warfarin or clopidogrel for another reason) continue for a minimum of 6 months.

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Risk of RV Failure

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No change in RV parameters between 6 and 12 months

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Summary

• LA overload/dysfunction is an important driver of worsening outcomes in HF, especially HFpEF

• IASD treatment has the potential to improve exercise tolerance and reduce adverse CV events

• Corvia ASD currently being studied in a large-scale, pivotal RCT (with exercise hemodynamics)

• Rigorous patient selection is critical to target the right patients to IASD therapy

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March 12, 2019

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V-Wave Shunt

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JACC CardiovascInterv. 2018;11:2300-2310 23

Initial Experience with the V-wave Shunt

• Special Access Program – 22 patients enrolled at 1 center in Canada

• First-In-Man Multicenter Feasibility Study- 16 patients enrolled in 5 centers in Israel and Spain

• Follow-up - 38 patients implanted (30 HFrEF, 8 HFpEF) with a median follow-up: 28 months (range: 18-48 months)

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JACC CardiovascInterv. 2018;11:2300-2310 24

Baseline Demographics

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Procedural and Safety Outcomes

• Shunt successfully implanted in 38/38 patients.

• Device or procedure related

MACNE at 3M and 12M: 2.6%.

• All cause MACNE at 12M: 7.9%.

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Functional, Echo and Hemodynamic Parameters

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Shunt Patency at 1,3 and 12 months (TEE)

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• Shunt patency at 1-3 months: 36/36 (100%) • 12-month shunt occlusion: 5/36 (14%) • 12-month shunt stenosis (TEE Color Doppler vena contracta in valve

region narrowed/skewed): 13/36 (36%) • No thrombus, no shunt migration, no erosion of adjacent structures

Pathological Examination (Stenotic Shunt)

• Explant at 2.5 years • LA view. Orifice widely patent.

• RA view. Pannus thickening with

stenosis of bioprosthetic leaflets.

• Axial Section (H&E). Fibrocellular neoendocardium (pannus) infiltration of leaflets.

• SEM. Full endothelialization of lumen (CD31+)

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Hemodynamic Changes Grouped by Shunt Patency at 1-Year Follow-Up

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JACC CardiovascInterv. 2018;11:2300-2310 30

Cumulative Clinical Events (all patients)

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JACC CardiovascInterv. 2018;11:2300-2310 31

Long-term Clinical Outcomes Grouped by Shunt Patency

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V-Wave Shunt: Initial Clinical Conclusions

• Interatrial shunting with the V-Wave system for treating patients with HFrEF and HFpEF was feasible, safe, and associated with promising efficacy data in terms of functional improvement and reduction of cardiovascular events

• There was a high frequency of shunt stenosis/occlusion at 1-year follow-up, likely secondary to pannus infiltration of the bioprosthetic leaflets, which associated with poorer hemodynamic and longer-term clinical outcomes

• Shunt patency was associated with sustained low morbidity and mortality

• Implementing modifications to improve device patency over time while maintaining hemodynamic and functional benefits is worthwhile prior to launching a randomized trial to confirm these findings

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JACC CardiovascInterv. 2018;11:2300-2310 33

V-Wave Shunt (Current Valveless)

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Valveless Shunts: No late lumen loss Data from non-diseased juvenile ovine model (2-3 mmHg L-R gradient)

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JACC CardiovascInterv. 2018;11:2300-2310 35

Valveless Shunts: Clinical Data -

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• 9 patients • Serial

echocardiography exams up to 1-year follow-up

• No shunt stenosis/occlusion

RELIEVE-HF RCT Design US FDA IDE approval

• Design • RCT, double-blind (patient and HF team) • 400 randomized and 100+ roll-in patients at up to 75 sites (US, Canada, EU and

Israel) • Primary Outcome measured at 24 months or until the last patient has been

followed for 12 months • Adaptive design with interim analysis and allowed expansion up to 600

randomized patients

• Study Population • NYHA functional class III or ambulatory class IV HF irrespective of left

ventricular ejection fraction, with history of HF hospitalization or elevated BNP/NT-pro BNP, in the setting of GDMT

• Endpoints • Primary Effectiveness: Finkelstein-Schoenfeld hierarchical comparison of

mortality, transplant/LVAD, HF hospitalization or equivalent, and 6MWT • Primary Safety: Performance criteria for device-related MACNE • Health economic metrics

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RELIEVE-HF RCT design overview

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RELIEVE-HF Patient Population Inclusion Criteria

1. Ischemic or non-ischemic cardiomyopathy with either reduced or preserved LV ejection fraction and documented heart failure for at least 6 months.

2. NYHA Class III or ambulatory Class IV. 3. On stable doses of maximally tolerated Class-1 guideline-directed

medical therapy (GDMT)including ACE/ARB/ARNI, BB, and MRA in HFrEF. 4. CRM Device therapy per Class I guidelines. 5. HF hospitalization within 12 months or corrected elevated BNP/NT-

proBNP (300/1500 pg/ml). 6. Able to perform the 6-minute walk test with a distance ≥100 meters and

≤450 meters. 7. Provide written informed consent for study participation and be willing

and able to comply with the required tests, treatment instructions and follow-up visits.

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RELIEVE-HF Patient Population Selected Exclusion Criteria

1. BMI >40 or <18 kg/m2. 2. Resting SBP <90 or >160 mmHg after repeated measurements 3. Baseline echo evidence of intracardiac thrombus 4. Severe pulmonary hypertension (PASP >70 mmHg by echo) 5. RV dysfunction defined as TAPSE <12mm or RVFAC ≤30%. 6. Left Ventricular End-Diastolic Diameter (LVEDD) >8cm. 7. ASD, PFO, or anomalous pulmonary venous return 8. Untreated moderate to severe aortic or mitral stenosis 9. Untreated severe (3+ to 4+) AR/MR (expect intervention in 12 months) 10. Acute MI, ACS, PCI, rhythm mgmt. system revision, lead extraction, or

cardiac or other major surgery within 3 months 11. Stroke, TIA, thromboembolism, or DVT within past 6 months. 12. Any prior stroke with permanent neurologic deficit. Any IVC filter.

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