Clinical Spotlight on Novel

Interventions for Patients with

Heart Failure
Clyde W. Yancy, MD, MSc, MACC, FAHA, MACP
Vice-Dean, Diversity & Inclusion
Magerstadt Professor of Medicine
Professor, Department of Medical Social Sciences
Chief of Cardiology
Northwestern University,
Feinberg School of Medicine
Associate Medical Director
Bluhm Cardiovascular Institute
Chicago, IL

Disclosures

Consultant/speaker/honoraria: none
JAMA Cardiology, Deputy Editor; ; Journal of the American College of
Cardiology- associate editor (HF); American Journal of Cardiology associate editor; : American Heart Journal, Circulation; Circulation-Heart
Failure- editorial boards
Guideline writing committees: Chair, ACC/AHA, chronic HF; member,
atrial fibrillation; member, Syncope; Chair, Performance Measures,
Sudden Cardiac Death
Federal appointments: FDA: Immediate Past Chair, Cardiovascular
Device Panel; ad hoc consultant; NIH Scientific Management and
Review Board; AHRQ- adhoc consultant; NHLBI- consultant; PCORImethodology committee member; IOM- writing group member
Volunteer Appointments: American Heart Association- President,
American Heart Association, 2009-2010; American College of Cardiology,
Founder- CREDO
2

Heart Failure Epidemiology

US Statistics
5.7 million persons currently diagnosed with HF
2.7 million males; 3.0 million females
870,000 new HF diagnoses annually
HF with preserved ejection fraction (HFpEF) occurs
in 55% of symptomatic HF cases
HF incidence is 10 per 1,000 patients older than 65
years
1.02 million discharges per year with primary diagnosis
of HF
Health care expenditure for HF was $30.7 billion in
2012
Mozaffarian D, et al. Circulation. 2015;131:e29-e322.

First Heart Failure Events in the US

Mozaffarian D, et al. Circulation. 2015;131:e29-e322.

Hospital Discharge Rates for HF

in the US

Mozaffarian D, et al. Circulation. 2015;131:e29-e322.

A Contemporary Appraisal of the

Heart Failure Epidemic
JAMA Internal Medicine 2015
Roger, Veronique
Age- and sex-specific incidence of heart failure has declined
315/100,000 to 219/100,000
Rate reduction of 37.5%
Incidence decline was greater for HFrEF 45.1% vs. HFpEF -27.9%
Risk for CV death was lower for HFpEF but the same for non-CV
death
Hospitalizations have increased 34%
Most hospitalizations, 63%, were due to non-cardiovascular causes
Thus todays epidemic of heart failure is defined by marked
increase in hospitalizations, predominance of non-CV death rate,
and persistence and predominance of HFpEF
6

HF: Classification of Disease

ACC/AHA
Stages

NYHA
Functional
Classification

7
Yancy CW et al. Circulation. 2013;128:e240-e327.

LIFESTYLE ADAPTATIONS:
Sodium and Water Restriction in HF
Sodium Restriction

Water restriction

Discussions should be patientcentered

When considered appropriate,
sodium restriction is deemed a
Class IIa recommendation
Sodium restriction is reasonable
for some patients with
symptomatic HF to reduce
congestive symptoms. (Level of
Evidence: C)
More data are needed to
determine the correct threshold of
sodium restriction

Should be considered but not

needed for all patients; Class IaI
recommendation
Fluid restriction (1.5-2.0 L/d) is
reasonable in stage D, especially
in patients with hyponatremia, to
reduce congestive symptoms.
(Level of Evidence: C)

Yancy CW, et al; ACCF/AHA Task Force on Practice Guidelines.

Circulation.2013;128:e240-e327.

Arginine vasopressin antagonists may

also be indicated for volume overload
states associated with profound
hyponatremia

Stages, Phenotypes, and Treatment of HF

At Risk for Heart Failure

Heart Failure

STAGE A

STAGE B

STAGE C

At high risk for HF but

without structural heart
disease or symptoms of HF

Structural heart disease

but without signs or
symptoms of HF

Structural heart disease

with prior or current
symptoms of HF

e.g., Patients with:

HTN
Atherosclerotic disease
DM
Obesity
Metabolic syndrome
or
Patients
Using cardiotoxins
With family history of
cardiomyopathy

Structural heart
disease

e.g., Patients with:

Previous MI
LV remodeling including
LVH and low EF
Asymptomatic valvular
disease

Development of
symptoms of HF

e.g., Patients with:

Known structural heart disease and
HF signs and symptoms

HFpEF
THERAPY
Goals
Heart healthy lifestyle
Prevent vascular,
coronary disease
Prevent LV structural
abnormalities
Drugs
ACEI or ARB in
appropriate patients for
vascular disease or DM
Statins as appropriate

THERAPY
Goals
Prevent HF symptoms
Prevent further cardiac
remodeling

Drugs
ACEI or ARB as
appropriate

Beta blockers as
appropriate

In selected patients
ICD
Revascularization or
valvular surgery as
appropriate

STAGE D
Refractory HF

THERAPY
Goals
Control symptoms
Improve HRQOL
Prevent hospitalization
Prevent mortality
Strategies
Identification of comorbidities
Treatment
Diuresis to relieve symptoms
of congestion
Follow guideline driven
indications for comorbidities,
e.g., HTN, AF, CAD, DM
Revascularization or valvular
surgery as appropriate

Refractory
symptoms of HF
at rest, despite
GDMT

e.g., Patients with:

Marked HF symptoms at
rest
Recurrent hospitalizations
despite GDMT

HFrEF
THERAPY
Goals
Control symptoms
Patient education
Prevent hospitalization
Prevent mortality
Drugs for routine use
Diuretics for fluid retention
ACEI or ARB
Beta blockers
Aldosterone antagonists
Drugs for use in selected patients
Hydralazine/isosorbide dinitrate
ACEI and ARB
Digoxin
In selected patients
CRT
ICD
Revascularization or valvular
surgery as appropriate

THERAPY
Goals
Control symptoms
Improve HRQOL
Reduce hospital
readmissions
Establish patients endof-life goals
Options
Advanced care
measures
Heart transplant
Chronic inotropes
Temporary or permanent
MCS
Experimental surgery or
drugs
Palliative care and
hospice
ICD deactivation

Pharmacologic Treatment for

Stage C HFrEF
HFrEF Stage C
NYHA Class I IV
Treatment:

Class I, LOE A
ACEI or ARB AND
Beta Blocker

For all volume overload,

NYHA class II-IV patients

For persistently symptomatic

African Americans,
NYHA class III-IV

For NYHA class II-IV patients.

Provided estimated creatinine
>30 mL/min and K+ <5.0 mEq/dL

Add

Add

Add

Class I, LOE C
Loop Diuretics

Class I, LOE A
Hydral-Nitrates

Class I, LOE A
Aldosterone
Antagonist

10

Medical Therapy for Stage C HFrEF:

Magnitude of Benefit Demonstrated in RCTs
RR Reduction
in Mortality

NNT for Mortality

Reduction
(Standardized to
36 mo)

RR Reduction
in HF
Hospitalizations

ACE inhibitor or
ARB

17%

26

31%

Beta blocker

34%

41%

Aldosterone
antagonist

30%

35%

Hydralazine/nitrate

43%

33%

GDMT

Fonarow, G, Yancy C. American Heart Journal, 2012.

11

The newest
Paradigms in HF

The Role of Heart Rate in

Cardiovascular Disease
Elevated heart rate
+

Atherosclerosis
Endothelial dysfunction
Oxidative stress
Plaque stability
Arterial stiffness
+

Ischemia
Oxygen consumption
Duration of diastole
Coronary perfusion

Chronic heart failure

Oxygen demand
Ventricular efficiency
Ventricular relaxation
+

Remodeling
Cardiac hypertrophy

13

Novel Interventions for Patients with Heart Failure

Ivabradine

Acts by inhibiting the If channel,

present in the cardiac SA node
Reduces persistently elevated
heart rate

SA node

Approved by FDA in April 2015 for

stable HF pts who have a resting
+
HR of at least
70 bpm, and who
are also taking the highest
tolerable dose of a beta blocker

DiFrancesco D. Curr Med Res Opin. 2005;21:1115-1122.

14

SHIFT Trial Inclusion Criteria

Inclusion criteria
Symptomatic chronic heart failure; NYHA class II IV
Admitted to hospital within 12 months before randomization
Left ventricular ejection fraction of 35% or lower
Normal sinus rhythm
Heart rates of 70 bpm or higher

Bohm M, et al. Lancet. 2010;376:886-894.

15

Background: Beta-blocker Treatment

Adapted from: Bohm M, et al. Lancet. 2010;376:886-894.

Adapted from: Swedberg K, et al. Lancet. 2010;376:875-885.

16

SHIFT: Ivabradine Reduces

Hospitalization for HF

Swedberg K, et al. Lancet. 2010;376:875-885.

17

SHIFT: Ivabradine Does Not Reduce

Cardiovascular Death

Swedberg K, et al. Lancet. 2010;376:875-885.

18

PARADIGM HF Trial

McMurray JJ, Packer M, Desai AS, et al. N Engl J Med. 2014;371(11):993-1004.

19

Simplified Schematic of the Renin

AngiotensinAldosterone System

von Lueder TG, et al. Circ Heart Fail. 2013;6:594-605.

20

Simplified Schematic of the Natriuretic

Peptide System (NPS)

21
von Lueder TG, et al. Circ Heart Fail. 2013;6:594-605.

Cardiac Antiremodeling Effects of

Angiotensin Receptor Neprilysin Inhibitors
(ARNi) in vitro and in vivo

von Lueder TG, et al. Circ Heart Fail. 2013;6:594-605.

22

Mechanism of Action of LCZ696

23

PARADIGM HF

McMurray JJ, Packer M, Desai AS, et al. N Engl J Med. 2014;371(11):993-1004.

24

PARADIGM-HF
(Prospective Comparison of ARNI with ACEI to
Determine Impact on Global Mortality and Morbidity in
Heart Failure trial)
Primary composite outcome
HR: 0.80 (0.73, 0.87) p = 0.0000004
Death from CV causes
20% risk reduction

HF hospitalization
21% risk reduction

P = 0.00008

P = 0.00008

693
658
558
537

25
McMurray JJ, Packer M, Desa i AS, et al. N Engl J Med. 2014;371(11):993-1004.

PARADIGM-HF
(Prospective comparison of ARNI with ACEI to
Determine Impact on Global Mortality and morbidity in
Heart Failure trial)

Cumulative Proportion of Patients

Who Died from Any Cause (%)

Death from any cause

40

16% risk reduction

HR: 0.84 (0.76, 0.93)

P = 0.0009

30

835
Enalapril
(n=4212)

711

20
LCZ696
(n=4187)

10

0
0

180

360

540

720

900

1080

1260

Days after Randomization

McMurray JJ, Packer M, Desai AS, et al. N Engl J Med. 2014;371(11):993-1004.

26

KaplanMeier Curve for the Time to First

Hospitalization for Heart Failure During First 30 Days
After Randomization, According to Study Group
Death from any cause

Packer M, et al. Circulation. 2015;131(1):54-61.

27

Cumulative Number of Hospitalizations for

Heart Failure in the Enalapril and LCZ696
Groups per 100 Patients
Death from any cause

Packer M, et al. Circulation. 2015;131(1):54-61.

28

Mean Baseline Characteristics of Patients with

Heart Failure and a Reduced Ejection Fraction in
Five Trials
Death from any cause

Jessup M. N Engl J Med. 2014. DOI: 10.1056/NEJMe1409898

29

Pharmacologic Treatment for Stage C HFrEF

Death from any

HFrEF Stage C
NYHA Class I IV
cause
Treatment:

ARNI
Class I, LOE A
ACEI or ARB AND
Beta Blocker

Ivabradine?

For all volume overload,

NYHA class II-IV patients

For persistently symptomatic

African Americans,
NYHA class III-IV

For NYHA class II-IV patients.

Provided estimated creatinine
>30 mL/min and K+ <5.0 mEq/dL

Add

Add

Add

Class I, LOE C
Loop Diuretics

Class I, LOE A
Hydral-Nitrates

Class I, LOE A
Aldosterone
Antagonist

30

HFpEF:
Heart Failure with Preserved
Ejection Fraction

Heart Failure with Preserved LV

Systolic Function
About 50% of patients with symptomatic HF have
preserved LVEF
Accounts for 40% of HF hospitalizations
More common in women, elderly, and obese, and
those with concomitant hypertension, LVH, or diabetes
Annual mortality rate is now thought to be similar to
that of patients with systolic HF
Paucity of clinical trial data to guide management
of HFpEF patients
Kitzman DW, et al. Am J Cardiol. 2001;87:413-419.
Redfield MM, et al. JAMA. 2003;289:194-202.
Vasan RS, et al. J Am Coll Cardiol. 1999;33:1948-1955.

32

Prevalence of Heart Failure with Preserved

Systolic Function in Men and Women
Cardiovascular Health Study
Men

Women
10%

31%

42%

23%
67%

27%
LVEF = left ventricular ejection fraction
Kitzman DW, et al. Am J Cardiol. 2001;87:413-419.

Normal (LVEF 55%)

Mild (LVEF 45%-54%)
Mod/severe (LVEF <45%)

33

Trends in Prevalence of HFpEF

Owan TE, et al. N Engl J Med. 2006;355(3):251-259.

34

Survival Outcomes of HFpEF and HFrEF

Number at Risk
Reduced ejection fraction
Preserved ejection fraction

Owan TE, et al. N Engl J Med. 2006;355(3):251-259.

35

Treatment of HFpEF
Recommendations

Recommendations

COR
COR

LOE
LOE

Systolic and diastolic blood pressure should be controlled according to

published clinical practice guidelines

Diuretics should be used for relief of symptoms due to volume overload

Coronary revascularization for patients with CAD in whom angina or

demonstrable myocardial ischemia is present despite GDMT

IIa

Management of AF according to published clinical practice guidelines

for HFpEF to improve symptomatic HF

IIa

Use of beta-blocking agents, ACE inhibitors, and ARBs for hypertension

in HFpEF

IIa

ARBs might be considered to decrease hospitalizations in HFpEF

IIb

III: No
Benefit

Nutritional supplementation is not recommended in HFpEF

Yancy CW, et al. Circulation. 2013;128:e240-e327.

36

Surgery and Devices

Heart monitoring devices
Implantable monitors
ICD and CRT
Heart replacement therapies
Mechanical circulatory support
Heart Transplantation
Heart valve repair/replacement
Surgery
Transcutaneous
37

The future is promising

Greater use of biomarkers
Multiple regenerative therapies
Stem cells (mesenchymal)
Gene transfer
Growth factors
Community engagement

38