Advanced Heart Failure Improving Outcomes with Current Therapies

Ravinder Kumar, MD, FACC

Feb 10, 2018

Disclosure

• Employee-Iowa Heart Center/Mercy-Des Moines

Learning Objectives

• Burden of Heart Failure

• Staging of HF

• Overview of therapies available for various stages of HF

• Advances in Heart Failure therapy

• Advanced Heart Failure – Definition

– Risk stratification

– Therapies

Burden of HF

• 5.7 million Americans ≥20 years of age have HF • Projected prevalence of HF will increase 46% from

2012 to 2030 • Lifetime risk of developing HF is 20% for Americans ≥40

years of age • 870,000 new HF cases annually • In 2013, HF costs in the United States exceeded $30

billion • Most common cause of hospitalization

– Primary diagnosis in >1 million hospital discharges – Readmission rates 20-25%

Clyde W. Yancy et al. Circulation. 2013;128:e240-e327

Definition of HF

• HF is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood

• The cardinal manifestations of HF

– dyspnea and fatigue leading to limited exercise tolerance

– fluid retention leading to pulmonary and/or splanchnic congestion and/or peripheral edema

Classification of HF

Clyde W. Yancy et al. Circulation. 2013;128:e240-e327

Stages of HF and NYHA functional class

Clyde W. Yancy et al. Circulation. 2013;128:e240-e327

Stages in the development of HF and recommended therapy by stage.

Clyde W. Yancy et al. Circulation. 2013;128:e240-e327

Clyde W. Yancy et al. JACC 2017;70:776-803

Heart Failure Pathway Writing Committee et al. JACC

Trial Evidence for Mortality Benefit of Drugs in HF

Beta blocker

Mineralocorticoid receptor

antagonist ACE

inhibitor

Angiotensin receptor blocker

Drugs that inhibit the renin-angiotensin system have modest effects on

survival

Based on results of SOLVD-Treatment, CHARM-Alternative,

COPERNICUS, MERIT-HF, CIBIS II, RALES and EMPHASIS-HF

10%

20%

30%

40%

0%

% D

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in

Mo

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lity

Drugs That Reduce Mortality in Heart

Failure With Reduced Ejection Fraction

PARADIGM-HF

RAAS and Natriuretic peptide system

RAAS and Natriuretic peptide system

Angiotensin receptor Neprilysin Inhibitor

2 weeks 1-2 weeks 2-4 weeks

Single-blind run-in period Double-blind period

(1:1 randomization)

Enalapril

10 mg BID

100 mg BID

200 mg BID

Enalapril 10 mg BID

LCZ696 200 mg BID

Randomization

LCZ696

PARADIGM-HF Study Design

McMurray JJV et al. N Engl J Med 2014;371:993-1004

PARADIGM-HF

McMurray et al. NEJM 2014

10%

20%

30%

40%

ACE inhibitor

Angiotensin receptor blocker

0%

% D

ec

rea

se

in

Mo

rta

lity

18%

20%

Effect of ARB vs placebo derived from CHARM-Alternative trial

Effect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial

Effect of LCZ696 vs ACE inhibitor derived from PARADIGM-HF trial

Angiotensin neprilysin inhibition

15%

LCZ696 Doubles Effect on CV Mortality

10%

20%

30%

40%

ACE inhibitor

Angiotensin receptor blocker

0%

% D

ec

rea

se

in

Mo

rta

lity

18%

20%

Effect of ARB vs placebo derived from CHARM-Alternative trial

Effect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial

Effect of LCZ696 vs ACE inhibitor derived from PARADIGM-HF trial

Angiotensin neprilysin inhibition

15%

LCZ696 Doubles Effect on CV Mortality

NNT to Reduce any cause Mortality

Jessup M. N Engl J Med 2014;371:1062-1064.

Lancet 2010; 376: 875–85

SHIFT Trial

Lancet 2010; 376: 875–85

2017 ACC/AHA/HFSA update

Lancet 2011; 377: 658–66

Device Therapy - ICD & CRT

Clyde W. Yancy et al. Circulation. 2013;128:e240-e327

Advanced HF/Stage D HF

ESC Definition of Advanced HF

Identifying Patients With Advanced HF

INTERMACS Profiles

Modifiers: Frequent flyer: for Profile 3-6 Arrhythmia TCS(temporary circulatory support) for profile 1-3

Tools for Prognostication

When “optimal medical therapy” fails, what are the options?

• Inotropes

• Mechanical circulatory support

• Heart Transplant

• Clinical Trials

• Palliative Care

D Refractory

Heart

Failure

ACT - Advanced Cardiac Therapies

Yancy C, et. al. Circ. 2013;128:e240-e327

Milrinone: Bridge to Transplant

• 60 milrinone-dependent patients, listed for transplant • 76% successfully bridged with milrinone (waited 59 days for txp) • 24% required LVAD (waited 93 days for txp) • 5 died (waited 130 days for txp)

J. Cardiac Failure 2008; 14(10): 839-843

Continuous Outpatient Support with Inotropes: Palliation

• 36 patients – Inotrope-dependent

– Refused/ineligible for transplant

• Rehospitalizations infrequent

• Infection/sepsis common

• Survival 3.4 months – Most died at home

J. Cardiac Failure 2003; 9(3): 180-187

Chronic inotrope infusion associated with high mortality

• OPTIME-CHF and PROMISE

• Randomized, double blinded

• 1000 patients/ea randomized to milrinone or placebo

• High rates of hypotension, arrhythmia, syncope

• 53% increase in mortality – Pts not “wet and cold”

– Inotropic therapy was not considered essential for management

JAMA 2002; 287(12): 1541-1547

NEJM 1991; 325: 1468-1475

Heart Transplant COR I

• Cardiac transplantation is considered the gold standard for the treatment of refractory end-stage HF.

• First successful cardiac transplantation in 1967

• Over last 50 years post transplant survival has improved

• Post transplant survival at 1-, 3-, and 5-year is 87.8%, 78.5%, and 71.7% in adults, respectively

Heart Transplant

Status at time of transplant impacts post-transplant survival

Barge-Caballero Circ Heart Failure. 2013

Heart Transplant Trends

JHLT 2011 Oct; 30(10): 1071-1132

Unmet Need in Advanced HF

• 150,000-300,000 patients 2000 heart transplants

+ 1500 VAD implants

• --------------------------------

= more pts need referrals!

HM III LVAD

Heartmate II (axial flow) HVAD

Syncardia TAH

MCS • BTT • Bridge to recovery • Destination therapy

Improvement in Survival with LVADs

N Engl J Med 2009;361:2241-51

N Engl J Med 2001;345:1435-43

REMATCH

2001

HVAD ADVANCE BTT Trial

Keith D. Aaronson et al. Circulation. 2012;125:3191-3200

Quality of Life

Rogers JG, Aaronson KD, Boyle AJ et al, JACC, 2010;55:1826-34.

Change in NYHA Class After HMII

Six Month

Follow-up for

BTT Patients

Two Year

Follow-up for

DT Patients

Change in Quality of Life

After HeartMate II:

MLWHF*

Survival Post LVAD implant

2017 INTERMACS Report. J HeartLungTransplant2017;36:1080–1086

J HeartLungTransplant2015;34:1495–1504

Optimal timing of ACT referral

J Am Coll Cardiol 2015;66:1747–61

INTERMACS Profiles

ROADMAP study

1 2 3 4 5 6 7 INTERMACS Profiles

CMS Coverage: Class IV

FDA Approval: Class IIIB/IV

Currently Not Approved Limited Adoption Acceptance

NYHA Class III Class

IIIB

Class IV

(Ambulatory)

Class IV

(On Inotropes)

1.0% 1.4% 3.0% 14.6% 29.9% 36.4% 14.3% Percent of current

implants in INTERMACS

ROADMAP Study

Jerry D. Estep et al. JACC 2015;66:1747-1761

Jerry D. Estep et al. JACC 2015;66:1747-1761

Common VAD complications

Events/100 pt months • Bleeding (17-24) • Thromboembolism

(1.5-2.5) • Neurologic events (2-

4) • Infection (11-28) • Mechanical failure

(0.8-3) • Right heart failure

(2.2-3.1)

Kirklin et. al. Second INTERMACs annual report. JHLT 29 (1), 2009

N Engl J Med 2014;370:33-40

LVAD Thrombosis

N Engl J Med 2014;370:33-40

HeartMate III LVAD

N Engl J Med 2017;376:440-50.

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Contraindications to Advanced Heart Failure Therapies

• Irreversible kidney, liver, neurologic dz

• Uncorrectable, severe PVD

• Active infection

• Severe psychosocial concerns

– Inadequate social support system

– Ongoing alcohol or substance abuse

• Medical nonadherence

• Other life-limiting disease

Contraindications to Heart Transplant (but not DT VAD)

• Advanced age (> 70-75)

• Morbid obesity (BMI > 40)

• Substance abuse

• PVR > 5

Goals of an assessment of candidacy for ACT

• Identify medical appropriateness (is the pt sick enough?)

• Identify social appropriateness

• Identify contraindications, opportunities for management

• Estimate prognosis

• Risk stratify

– Intermacs profile, DT risk score, MELD

• Determine which therapy is right for the individual patient

– Inotropes, VAD, heart transplant, palliative care, something else

• Educate

• Informed consent – shared decision making

Eur Heart J. 2015;36(48):3467-3470

Eur Heart J. 2015;36(48):3467-3470.

Summary

• Heart failure prevalence/incidence is increasing

• Post transplant survival has improved over last 50 years

• Scarcity of donors led to development of durable MCS devices

• Durable MCS devices have improved survival and quality of life in patients with advanced heart failure

Thank you