Navin K. Kapur, MD, FACC, FSCAI, FAHA

Associate Professor, Department of Medicine

Interventional Cardiology & Advanced Heart Failure Programs

Executive Director, The Cardiovascular Center for Research & Innovation

Understanding the Importance of Ventricular Unloading in Management of AMI and

Cardiogenic Shock (Clinical Trial Results)

Relevant Disclosures

Research Funding & Speaker/Consulting Honoraria:

Abiomed, Abbott, Boston Scientific, Maquet, Medtronic, MD Start, Cardiac Assist

Herbert J. Levine

Foundation

Tufts Medical Center

RO1HL139785, RO1H133215

Charlton Award

Tufts Medical Center

First, Let’s Define What LOAD means

Heart RateLV Wall Stress (P/2rh)LV Systolic PressureLV Diastolic Pressure

LV Stroke Work

Coronary OcclusionCollateral Blood FlowMultivessel Disease

Microvasc DysfunctionSystemic Hypotension

Myocardial

Oxygen Supply

Myocardial

Oxygen Demand

Load refers to any variable that increases

myocardial oxygen consumption (demand)

LVEDP (>18mmHg) is associated with increased

incidence of heart failure in STEMI

Second, Why is LOAD BAD in Acute MI?

Kirtane and Gibson 2004 J Thromb Thromb

LVEDP (>18mmHg) is associated with reduced

coronary flow and myocardial perfusion

Kirtane and Gibson 2004 J Thromb Thromb

Second, Why is LOAD BAD in Acute MI?

LVEDP (>24mmHg) is associated with increased

mortality in STEMI

Planer and Stone 2011 Am J Card

Second, Why is LOAD BAD in Acute MI?

Systolic BP-to-LVEDP Ratio and In-hospital Mortality

Sola and Yeung 2017 CCI

Second, Why is LOAD BAD in Acute MI?

SBP

LVEDP< 4

LOAD is BAD in Acute MI, but it is WORSE in SHOCK

Forrester-Diamond-Swan Classification (1977)

Cardiac Index and PCWP are associated with mortality

Second, Let’s Understand Why LOAD is

BAD in Acute Myocardial Infarction

Acute Myocardial Infarction With or Without Shock is

Associated with Increased LV Wall Stress

Volume

Pre

ssure

Cardiogenic

Shock

How about UNLOADING in AMI/Shock?

Now, Let’s Define UNLOADING in Shock

Heart RateLV Wall Stress (P/2rh)LV Systolic PressureLV Diastolic Pressure

LV Stroke Work

Coronary OcclusionCollateral Blood FlowMultivessel Disease

Microvasc DysfunctionSystemic Hypotension

Myocardial

Oxygen Supply

Myocardial

Oxygen Demand

Unloading refers to a reduction in

myocardial oxygen consumption (demand)

while maintaining systemic perfusion

Finally, Show me the RCTs Studying

Unloading Devices (Acute MCS) Trials

In Acute MI and Shock

IABP Shock II(IABP in AMI)

IMPRESS Trial(IABP vs CP in AMI-Shock)

Negative Trial

Negative Trial

VA-ECMO RCTs Do Not Exist

Impella RCTs Do Not Exist

Here are the Problems

No Algorithm + No Shock Stratification

AMI-Shock Management is Not Simple

INSERT

ANY DEVICE

HERE

Morine & Kapur et al. Shock Working Group

The

Door to Support

Time

Treat Shock Before Metabolic Failure Begins

Tufts Cardiogenic Shock Algorithm

Hemodynamically driven decision makingHemo-Metabolic Shock has a Poor Prognosis

Cardiogenic Shock Trials Should be

Testing Algorithms not a Specific Pump

O’Neill W. JIC 2013

Success in Cardiogenic Shock Requires

Early Initiation of Acute MCS

Courtesy of D. Burkhoff

Unloading Mechanistic Impact 1

Reduced LV Wall Stress & Myocardial O2 Consumption

Swain L, Qiao X, Reyet L, and Kapur NK et al 2019

IRI Impella ECMO

VA-ECMO Before Reperfusion Does Not Reduce

Infarct Size : Must Unload the LV

Unloading Mechanistic Impact 2

Unloading Increases Perfusion without Reperfusion

D. Burkhoff

Unloading Improves Myocardial Perfusion

Without the Need for Reperfusion

CFI

Seiler and Meier et al. JACC 1998; Lee and Park et al. JACC 2000

Poccl

Collateral Flow Index (CFI)

PaortaPump Activated

(LAD Occluded)

Annamalali, Briceno and Kapur NK et al. 2019

No Pump

Impella

VA-ECMO

Annamalali, Briceno and Kapur NK et al. 2019

Unloading Improves Myocardial Perfusion

Without the Need for Reperfusion

Unloading Shrinks the Area at Risk

Esposito, Zhang, Qiao and Kapur NK et al. JACC 2018

Primary Reperfusion Primary Unloading

Unloading Protects the Heart and

Sets the Stage for Myocardial Recovery

ReperfusionIschemia Unload

Beta-blockers and Afterload reduction

Unloading and Delaying Reperfusion Protects

Complex One in the Mitochondrial Power Plant

Swain & Kapur2019

Reperfusion Alone Primary Unloading

ReperfusionIschemia Unload

Unloading and Delaying Reperfusion Impacts

Fundamental Myocardial Biology

Swain & Kapur et al 2019

Electrocardiographic ConfirmationInformed Consent and Enrollment

Explant Impella CP after a minimum of 3 hours support

Anterior STEMI Referred for Primary PCI

Patient preparation, draping, anti-coagulation, anti-platelet therapy, ultrasound guided femoral access, vascular angiogram, left ventriculography, 14 French

sheath insertion, then Randomization to U-IR or U-DR

Impella CP Insertion + Activation

Tim

e is M

uscle

Door To Unload: STEMI Pilot Trial: Study Design

U-DR Group30 minutes of Unloading

U-IR GroupRadial (or femoral access), coronary

angiography, coronary wiring and angioplasty

Independent Data Safety Monitor, Electrocardiographic, Angiographic, and

Cardiac Magnetic Resonance Imaging Core Labs

Radial (or femoral access), coronary angiography, coronary wiring and

angioplasty

Kapur NK and O’Neill W et al Circulation 2018

A New Era for Cardiovascular Therapeutics

A Focus on Ventricular Unloading

Kapur NK and O’Neill W et al Circulation 2018

0

10

20

30

40

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Patients Enrolled

Impella

to P

CI T

ime (

min

s)

U-DR

34 mins

Average

U-IR

11 mins

Average

30 minutes of unloading

Successful enrollment & protocol completion

Zero Bailout PCI in the U-DR Group

Kapur NK and O’Neill W et al Circulation 2018

The Potential to Change the Game Exists

Kapur NK et al J Card Transl Res 2019

Unloading Diminishes the Impact of Ischemic DurationAmong Large Anterior STEMIs

193

163

34

11

U-DR

U-IR

Unload PCI

Unload PCI

227 mins

59.9%

U-IR U-DR

Infarct / AAR

Expected

N=14

Observed

44.1%

N=16

p = 0.04*

Symptom

OnsetTreatment Timeline (minutes) 64 mins of

ischemia

174 mins

STE>6 Group

Standard Infarct vs Time Slope

Expected w/ 60 min delay (223 mins)

Observed w/ Unload + 60 min delay (227 mins)

Expected w/ no delay (163 mins)

Time is Muscle (Tarantini 2005)

Unloaded Infarct vs Time Slope

Our Collective Focus:The Door to Unload Pivotal Trial

Goal: Establish safety & feasibility:

• Successful enrollment and

protocol completion (Feasibility)

• No increase in infarct

associated with 30 minute

delay (Safety)

• No increase in major adverse

cardiovascular or cerebral

events (MACCE Safety)

Aim: LV Unloading as an approach to

limit infarct size and reduce heart failure after STEMI

SAFETY & FEASIBILITY

HUMAN STUDY

Pivotal RANDOMIZED

CONTROLLED TRIALPRECLINICAL

• Test primary

hypothesis

• Study mechanism

• Determine optimal

timing of unloading

• Examine late

functional effect and

remodeling

Multicenter, RCT

in Anterior STEMI

DTU + 30 min Delay

versus

DTB: Standard of Care

Anticipated Launch in

2019

Education, Training, and Implementation of Best Practices to Achieve Safety

nkapur@tuftsmedicalcenter.org

Thank you

To Learn More about

Acute Mechanical Circulatory Support

Interventional Heart Failure

December 2019

Paris, France

August 2019, Paris, France