2016 Update to Heart Failure

Clinical Practice Guidelines

Tuesday August 2, 2016
1:00pm 2:00pm CST (60 minute webinar)

Presenters:
Dr. Gregg Fonarow, MD, FACC, FAHA, FHFSA
Dr. Clyde Yancy, MD, MSc, MACC, FAHA, MACP
Dr. Paul Heidenreich, MD, MS, FACC
 Clyde W. Yancy, MD, MSc, MACC, FAHA, MACP
Vice Dean, Diversity & Inclusion
Magerstadt Professor of Medicine
Professor of Medical Social Sciences
Chief, Division of Cardiology
Northwestern University, Feinberg School of Medicine
Associate Director, Bluhm Cardiovascular Institute

Gregg C. Fonarow, MD, FACC, FAHA Paul A Heidenreich, MD, MS,

The Eliot Corday Professor of Cardiovascular Medicine and FACC
Science Associate Professor of Medicine
Co-Chief of Clinical Cardiology UCLA Division of Vice-Chair for Clinical, Quality and Analytics,
Cardiology Department of Medicine
Director, Ahmanson-UCLA Cardiomyopathy Center Stanford University
Co-Director, UCLA Preventative Cardiology Program

8/2/2016 2013, American Heart Association

2
2016 Update to Heart Failure Clinical Practice Guidelines

New Epidemiology

New Therapies

New Guidelines

New Phenotype
From: A Contemporary Appraisal of the Heart Failure Epidemic in Olmsted County, Minnesota, 2000 to 2010

JAMA Intern Med. 2015;175(6):996-1004. doi:10.1001/jamainternmed.2015.0924

Figure Legend:
Temporal Trends in Heart Failure Incidence Rates Overall and by Reduced or Preserved Ejection Fraction Among Women and Men
in Olmsted County, Minnesota, 2000 to 2010Yearly rates (smoothed using 3-year moving average) per 100 000 persons have been
standardized by the direct method to the age distribution of the US population in 2010. HFpEF indicates heart failure with preserved
ejection fraction; HFrEF, heart failure with reduced ejection fraction.

Copyright 2016 American Medical

Association. All rights reserved.
Date of download: 6/10/2016
 A Contemporary Appraisal of the HF Epidemic
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 a marked increase in

hospitalizations, predominance of non-CV death rate, and persistence and
predominance of HFpEF Roger VL et al. JAMA Intern Med. 2015; April 20. Epub ahead of print.
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 Structural heart disease Structural heart disease STAGE D
without structural heart but without signs or with prior or current Refractory HF
disease or symptoms of HF symptoms of HF symptoms of HF

e.g., Patients with:

HTN
Atherosclerotic disease
e.g., Patients with: e.g., Patients with:
DM Refractory
Previous MI e.g., Patients with:
Obesity Development of symptoms of HF Marked HF symptoms at
Structural heart LV remodeling including Known structural heart disease and
Metabolic syndrome symptoms of HF at rest, despite rest
disease LVH and low EF HF signs and symptoms GDMT
or
Asymptomatic valvular Recurrent hospitalizations
Patients despite GDMT
disease
Using cardiotoxins
With family history of
cardiomyopathy

HFpEF HFrEF

THERAPY THERAPY THERAPY THERAPY THERAPY

Goals Goals Goals Goals Goals
Control symptoms Control symptoms
Heart healthy lifestyle Prevent HF symptoms Control symptoms Patient education Improve HRQOL
Prevent vascular, Prevent further cardiac Improve HRQOL Prevent hospitalization Reduce hospital
coronary disease remodeling Prevent hospitalization Prevent mortality readmissions
Prevent LV structural Prevent mortality Establish patients end-
abnormalities Drugs Drugs for routine use of-life goals
ACEI or ARB as Diuretics for fluid retention
Strategies ACEI or ARB Options
Drugs appropriate Identification of comorbidities Beta blockers Advanced care
ACEI or ARB in Beta blockers as measures
Aldosterone antagonists
appropriate Heart transplant
appropriate patients for Treatment
vascular disease or DM Diuresis to relieve symptoms Drugs for use in selected patients Chronic inotropes
In selected patients Hydralazine/isosorbide dinitrate Temporary or permanent
Statins as appropriate of congestion MCS
ICD ACEI and ARB
Revascularization or Follow guideline driven Digoxin Experimental surgery or
valvular surgery as indications for comorbidities, drugs
appropriate e.g., HTN, AF, CAD, DM In selected patients Palliative care and
Revascularization or valvular CRT hospice
ICD ICD deactivation
surgery as appropriate
Revascularization or valvular
surgery as appropriate

Yancy, C. Jessup M, Bozkurt B. et al. JACC 2013

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 persistently symptomatic For NYHA class II-IV patients.

For all volume overload,
African Americans, Provided estimated creatinine
NYHA class II-IV patients
NYHA class III-IV >30 mL/min and K+ <5.0 mEq/dL

Add Add Add

Class I, LOE A
Class I, LOE C Class I, LOE A
Aldosterone
Loop Diuretics Hydral-Nitrates
Antagonist

Yancy, C et al. JACC 2013

 Residual Risk for HFrEF Despite
Conventional GDMT

Of all patients randomized to enalapril, the

absolute risk of CV death as a first event
was 10.9% (n=459/4212)1

In PARADIGM-HF, study patients were followed over a median of 27 months.2,*

*Adult patients with NYHA class IIIV symptoms and an ejection fraction of 40% or
less were required to take a stable dose of a beta blocker and an ACE inhibitor (or
ARB) equivalent to at least 10 mg of enalapril daily, with most also receiving MRA.

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

Effects of Neprilysin Inhibition in Heart Failure
Endogenous Neurohormonal
vasoactive peptides activation
Vascular tone
(natriuretic peptides, adrenomedullin,
bradykinin, substance P, Cardiac fibrosis,
calcitonin gene-related peptide) hypertrophy
Sodium retention

Neprilysin
Neprilysin inhibition

Inactive metabolites

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

PARADIGM-HF: Primary Endpoint of CV Death or Heart
Failure Hospitalization
Number needed to treat = 21

1.0 HR 0.80 (95% CI,

Cumulative Probability
0.730.87), p<0.001
0.6
0.5
0.4 Enalapril
1117 events (26.5%)
0.3
0.2 Sac/Val
914 events (21.8%)
0.1
0
0 180 360 540 720 900 1080 1260
Days since Randomization
Number at
Risk 4187 3922 3663 3018 2257 1544 896 249
Sac/Val 4212 3883 3579 2922 2123 1488 853 236
Sac/Val = Sacubitril/Valsartan.
Enalapril
McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.
PARADIGM-HF: Effect of Sac/Val vs. Enalapril on the
Primary Endpoint and Its Components
Sac/Val Enalapril Hazard Ratio p-
(n=4187) (n=4212) (95% CI) Value

Primary 914 1117 0.80

<0.001
endpoint (21.8%) (26.5%) (0.730.87)

Cardiovascular 558 693 0.80

<0.001
death (13.3%) (16.5%) (0.710.89)

Hospitalization 537 658 0.79

<0.001
for heart failure (12.8%) (15.6%) (0.710.89)

Sac/Val = Sacubitril/Valsartan.
McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.
Sac/Val vs. Enalapril on Primary Endpoint and on CV Death by
Subgroups

Subgroup Sac/Val Enalapril Primary Endpoint Death from Cardiovascular Causes

Hazard Ratio p-Value for Hazard Ratio p-Value for
No. (95% CI) Interaction (95% CI) Interaction
All Patients 4187 4212
Age
<65 years 2111 2168 0.47 0.70
65 years 2076 2044
Sex
Male 3308 3259
0.63 0.92
Female 879 953
NYHA Class
I or II 3187 3130 0.03 0.76
III or IV 1002 1076
Estimated GFR
<60 mL/min/1.73 m2 1541 1520 0.91 0.73
60 mL/min/1.73 m2 2646 2692
Ejection fraction
35% 3715 3722 0.36 0.36
>35% 472 489
NT-proBNP
Median 2079 2116
0.16 0.33
>Median 2103 2087
Hypertension
No 1218 1241 0.87 0.14
Yes 2969 2971
Prior use of ACE inhibitor
No 921 946 0.09 0.06
Yes 3266 3266
Prior use of aldosterone antagonist
No 1916 1812 0.10 0.32
Yes 2271 2400
Prior hospitalization for heart failure
No 1580 1545
0.10 0.19
Yes 2607 2667

0.3 0.5 0.7 0.9 1.1 1.3 1.5 1.7 0.3 0.5 0.7 0.9 1.1 1.3 1.5 1.7

Sac/Val Better Enalapril Better Sac/Val Better Enalapril Better

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

PARADIGM-HF: Adverse Events
Sac/Val Enalapril p-
(n=4187) (n=4212) Value
Prospectively identified adverse events
Symptomatic hypotension 14.0% 9.2% <0.001
Serum potassium > 6.0 mmol/L 4.3% 5.6% 0.007
Serum creatinine 2.5 mg/dL 3.3% 4.5% 0.007
Cough 11.3% 14.3% <0.001
Discontinuation for adverse event 10.7% 12.3% 0.03
Discontinuation for hypotension 0.9% 0.7% 0.38
Discontinuation for hyperkalemia 0.3% 0.4% 0.56
Discontinuation for renal impairment 0.7% 1.4% 0.002
Angioedema (adjudicated)
Medications, no hospitalization 6 (0.1%) 4 (0.1%) 0.52
Hospitalized; no airway compromise 3 (0.1%) 1 (<0.1%) 0.31
Airway compromise 0 0

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

New FDA-Approved Sacubitril/Valsartan
Sacubitril/Valsartan
Brand name Entresto
The fixed-dose combination of the neprilysin inhibitor sacubitril and
Indication the ARB valsartan is indicated to reduce the risk of CV death and HF
hospitalization in patients with HF with reduced ejection fraction.
Start with 49/51 mg twice daily. Double the dose after 24 weeks as
Dosage
tolerated to maintenance dose of 97/103 mg twice daily.
For patients not currently taking an ACEI or ARB, or for those with
Renal/hepatic
severe renal impairment (eGFR <30 mL/min/1.73 m2) or moderate
impairment
hepatic impairment, start with 24/26 mg twice daily.
Switching from an
Stop ACE inhibitor for 36 hours before starting treatment.
ACE inhibitor
History of angioedema related to previous ACE inhibitor or ARB,
Contraindications concomitant use of ACE inhibitors, concomitant use of aliskiren in
patients with diabetes. WARNING pregnancy, hyperkalemia.
Hypotension, hyperkalemia, cough, dizziness, renal failure, and
Side effects
angioedema (0.5% Sac/Val vs. 0.2% Enalapril).

http://www.pdr.net/full-prescribing-information/entresto?druglabelid=3756. Accessed October 20, 2015.

Practical Points on Use of Sacubitril/Valsartan

Starting dose is 24/26 mg twice daily, unless patient is currently tolerating full
dose ACEI or ARB in which case start 49/51 mg twice daily

Target dose is 97/103 mg twice daily

After 2-4 weeks uptitrate to next dose with ultimate goal to achieve target dose

Monitor SBP, renal function and K as you would with ACEI or ARB use

Space out dosing from other vasoactive medications if needed

Adjust diuretics doses based on volume status

Ivabradine

Acts by inhibiting the If channel,

present in the cardiac SA node
Reduces persistently elevated heart
SA node
rate
Evaluated as treatment of HFrEF who
have a resting HR of at least 70 beats
per minute, in sinus rhythm, and who
are also taking the highest tolerable
dose of a beta blocker
DiFrancesco D. Curr Med Res Opin. 2005;21:1115-1122.
SHIFT Study: Primary Endpoint of CV Death or Hospitalization for
Worsening HF

40 Ivabradine (n=3241)
Placebo (n=3264)

Primary Endpoint (%)

Placebo
937 events (29%) 18%
30
Patients with

Ivabradine
20 793 events (24%)

10 HR 0.82 (95% CI, 0.750.90)

p<0.0001
ARR = 5%, NNT = 20
0
0 6 12 18 24 30
Months
Swedberg K, et al. Lancet. 2010;376:875-885.
SHIFT Study: Effect of Ivabradine on Outcomes

Ivabradine Placebo
Endpoint HR p-Value
(n=3241) (n=3264)
Primary endpoint 24% 29% 0.82 <0.0001
All-cause mortality 16% 17% 0.90 0.092
Death from HF 3% 5% 0.74 0.014
All-cause hospitalization 38% 42% 0.89 0.003
Any CV hospitalization 30% 34% 0.85 0.0002
CV death, hospitalization
for worsening HF, or
25% 30% 0.82 <0.0001
hospitalization for
non-fatal MI

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

New FDA-Approved Ivabradine
Ivabradine

Brand name Corlanor

To reduce the risk of hospitalization for worsening HF in patients with

stable, symptomatic chronic HF with LVEF 35% who are in sinus
Indication
rhythm with resting HR 70 bpm and either are on maximally tolerated
doses of beta-blockers or have a contraindication to beta-blocker use.

Start with 5 mg twice daily. After 2 weeks of treatment, adjust dose

based on HR. Max is 7.5 mg twice daily. In patients with conduction
Dosage
defects or in whom bradycardia could lead to hemodynamic
compromise, start with 2.5 mg twice daily.

Acute decompensated HF; BP <90/50 mmHg; sick sinus syndrome or

third-degree AV block, unless a functioning demand pacemaker is
Contraindications
present; resting HR < 60 bpm prior to treatment; severe hepatic
impairment; pacemaker dependence. WARNING fetal toxicity.

Occurring in 1% of patients are bradycardia, hypertension, atrial

Side effects
fibrillation, and luminous phenomena (phosphenes).

http://www.pdr.net/full-prescribing-information/corlanor?druglabelid=3713. Accessed October 20, 2015.

Practical Points on Use of Ivabradine

Starting dose is 5 mg twice daily

Target HR is 50-60 bpm

After 2 weeks:

If HR >60 bpm:
Increase dose to 7.5 mg twice daily (Max dose)

If HR 50-60 bpm:
Maintain initial dose

If HR <50 bpm or symptomatic bradycardia:

Lower dose to 2.5 mg twice daily

If HR <50 bpm or symptomatic bradycardia and dose is 2.5 mg twice daily: Discontinue
 Pharmacologic Treatment for
Stage C HFrEF
Strategies: HFrEF Stage C
Disease Management NYHA Class I IV
Treatment:
Remote PA monitoring
Process Improvement ? Valsartan/Sacubutril
Patient Education ? Ivabradine
Class I, LOE A
Frailty Assessment ACEI or ARB AND
Beta Blocker

Palliative Care
Genetic Counseling
For persistently symptomatic For NYHA class II-IV patients.
For all volume overload,
African Americans, Provided estimated creatinine
NYHA class II-IV patients
NYHA class III-IV >30 mL/min and K+ <5.0 mEq/dL

Add Add Add

Class I, LOE A
Class I, LOE C Class I, LOE A
Aldosterone
Loop Diuretics Hydral-Nitrates
Antagonist
New Guidelines Have Emerged- 2016
COR/LOE 2016
RAASi in Heart Failure and Post-MI LV Dysfunction

Post-MI Mild-Mod CHF CHF CHF

Low EF Low EF Severe HF Preserved EF

ACEi1 AIRE SOLVD CONSENSUS PEP-CHF

SAVE (perindopril)

EPHESUS1 EMPHASIS1 RALES1 TOPCAT2

MRA
(eplerenone) (eplerenone) (spironolactone) (spironolactone)

ARB1 OPTIMAAL ELITE-II CHARM-Preserved

VALIANT HEALL
VAL-HeFT I-PRESERVE
CHARM

PARADIGM-HF
ARNI3
(LCZ-696)
RAASi=renin-angiotensin-aldosterone inhibitor; MI=myocardial infarction; EF: ejection fraction; CHF=chronic heart failure;
ACEi=angiotensin-converting enzyme inhibitor; MRA=mineralocorticoid receptor antagonist; ARB=angiotensin II receptor
blocker; ARNI=angiotensin receptor-neprilysin inhibitor.

1. Mentz RJ, et al. Int J Cardiol. 2013:167:1677-1687.

2. Pitt B, et al. N Engl J Med. 2014;370(15):1383-1392.
3. McMurray JJV, et al. N Engl J Med 2014;371:993-1004.
RAAS inhibition- 2016
ACE-I & ARB- 2016
ARNI 2016
ARNI (Harm) 2016
Ivabradine 2016
ESC HF Guidelines 2016
ESC HFrEF Treatment Algorithm
A new classification?
ESC HF GUIDELINES 2016
Definition of Heart Failure- ACC/AHA 2013
Classification Ejection Description
Fraction
I. Heart Failure with 40% Also referred to as systolic HF. Randomized clinical trials have
Reduced Ejection mainly enrolled patients with HFrEF and it is only in these
Fraction (HFrEF) patients that efficacious therapies have been demonstrated to date.
II. Heart Failure with 50% Also referred to as diastolic HF. Several different criteria have
Preserved Ejection been used to further define HFpEF. The diagnosis of HFpEF is
Fraction (HFpEF) challenging because it is largely one of excluding other potential
noncardiac causes of symptoms suggestive of HF. To date,
efficacious therapies have not been identified.
a. HFpEF, Borderline 41% to 49% These patients fall into a borderline or intermediate group. Their
characteristics, treatment patterns, and outcomes appear similar to
those of patient with HFpEF.
b. HFpEF, Improved >40% It has been recognized that a subset of patients with HFpEF
previously had HFrEF. These patients with improvement or
recovery in EF may be clinically distinct from those with
persistently preserved or reduced EF. Further research is needed
to better characterize these patients.

Yancy C et al, JACC 2013

From: Characteristics and Outcomes of Adult Outpatients With Heart Failure and Improved or Recovered
Ejection Fraction
JAMA Cardiol. Published online July 06, 2016. doi:10.1001/jamacardio.2016.1325

Figure Legend:
Kaplan-Meier Curves, Adjusted for Age and Sex, Across the 3 Heart Failure GroupsThe stratified log-rank 22 was 15.0 (P<.001)
for difference in mortality between groups. HFpEF indicates heart failure with preserved ejection fraction; HFrecEF, heart failure with
recovered ejection fraction; and HFrEF, heart failure with reduced ejection fraction.

Copyright 2016 American Medical

Date of download: 7/11/2016 Association. All rights reserved.
A new HF phenotype 2016
From: Potential Mortality Reduction With Optimal Implementation of Angiotensin Receptor Neprilysin Inhibitor
Therapy in Heart Failure
JAMA Cardiol. Published online June 22, 2016. doi:10.1001/jamacardio.2016.1724

Table Title:
Demonstrated Benefits of Evidence-Based Therapies for Patients With Heart Failure and Reduced Ejection Fraction

Copyright 2016 American Medical

Date of download: 7/11/2016
Association. All rights reserved.
 Taking the failure out of HF - 2016
We can prevent the progression of HF

Greater use of biomarkers & imaging PREVENTION, diagnosis, prognosis & treatment ;early introduction of
RAAS inhibitors

GDMT for HFrEF & Quality Improvement

Still with untapped effectiveness

Device therapy (ICD/CRT) as indicated; now incl PA monitor?

New drug therapies-

LCZ696; Ivabradine

Personalized Therapy driven by Pharmacogenomics

- NO donors
Reversal of Disease

Stem cells (iPS, mesenchymal); Gene Transfer; Growth Factors

Gene Editing
 Questions?

Thank you!
8/2/2016 2013, American Heart Association 38
More Questions about Get With The Guidelines?
Visit heart.org/QualityHF to find your local Get With The Guidelines representative.

Liz Olson, CVA

Program Manager
Get With The Guidelines - Resuscitation & Heart Failure
liz.olson@heart.org I www.heart.org
Phone 214-706-1528

2013, American Heart Association 39