2016 Update to Heart FailureClinical 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

8/2/2016 ©2013, American Heart Association 2

Gregg C. Fonarow, MD, FACC, FAHAThe Eliot Corday Professor of Cardiovascular Medicine and ScienceCo-Chief of Clinical Cardiology UCLA Division of CardiologyDirector, Ahmanson-UCLA Cardiomyopathy CenterCo-Director, UCLA Preventative Cardiology Program

Clyde W. Yancy, MD, MSc, MACC, FAHA, MACPVice Dean, Diversity & InclusionMagerstadt Professor of MedicineProfessor of Medical Social SciencesChief, Division of CardiologyNorthwestern University, Feinberg School of MedicineAssociate Director, Bluhm Cardiovascular Institute

Paul A Heidenreich, MD, MS, FACC

Associate Professor of MedicineVice-Chair for Clinical, Quality and Analytics,

Department of MedicineStanford University

2016 Update to Heart Failure Clinical Practice Guidelines

• New Epidemiology

• New Therapies

• New Guidelines

• New Phenotype

Date of download: 6/10/2016

Copyright © 2016 American Medical Association. All rights reserved.

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

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.

Figure Legend:

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 today’s 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 HFSTAGE A

At high risk for HF but without structural heart

disease or symptoms of HF

STAGE BStructural heart disease

but without signs or symptoms of HF

THERAPYGoals• 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

STAGE CStructural heart disease

with prior or current symptoms of HF

THERAPYGoals• 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

STAGE DRefractory HF

THERAPYGoals• 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

e.g., Patients with:• Known structural heart disease and• HF signs and symptoms

HFpEF HFrEF

THERAPYGoals• 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

THERAPYGoals• Control symptoms• Improve HRQOL• Reduce hospital

readmissions• Establish patient’s end-

of-life goals

Options• Advanced care

measures• Heart transplant• Chronic inotropes• Temporary or permanent

MCS• Experimental surgery or

drugs• Palliative care and

hospice• ICD deactivation

Refractory symptoms of HF at rest, despite GDMT

At Risk for Heart Failure Heart Failure

e.g., Patients with:• Marked HF symptoms at

rest • Recurrent hospitalizations

despite GDMT

e.g., Patients with:• Previous MI• LV remodeling including

LVH and low EF• Asymptomatic valvular

disease

e.g., Patients with:• HTN• Atherosclerotic disease• DM• Obesity• Metabolic syndrome orPatients• Using cardiotoxins• With family history of

cardiomyopathy

Development of symptoms of HFStructural heart

disease

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

HFrEF Stage CNYHA Class I – IV

Treatment:

For NYHA class II-IV patients. Provided estimated creatinine

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

For persistently symptomatic African Americans, NYHA class III-IV

Class I, LOE AACEI or ARB AND

Beta Blocker

Class I, LOE CLoop Diuretics

Class I, LOE AHydral-Nitrates

Class I, LOE AAldosterone Antagonist

AddAdd Add

For all volume overload, NYHA class II-IV patients

Pharmacologic Treatment for Stage C HFrEF

Yancy, C et al. JACC 2013

Residual Risk for HFrEF Despite Conventional GDMT

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

*Adult patients with NYHA class II–IV 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.

Of all patients randomized to enalapril, the absolute risk of CV death as a first event was 10.9% (n=459/4212)1

Endogenousvasoactive peptides

(natriuretic peptides, adrenomedullin,bradykinin, substance P,

calcitonin gene-related peptide)

Inactive metabolites

Neurohormonal activation

Vascular tone

Cardiac fibrosis, hypertrophy

Sodium retention

Neprilysin Neprilysininhibition

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

Effects of Neprilysin Inhibition in Heart Failure

Sac/Val = Sacubitril/Valsartan. McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

Number needed to treat = 21

PARADIGM-HF: Primary Endpoint of CV Death or Heart Failure Hospitalization

Number at RiskSac/ValEnalapril

0 180 540 900Days since Randomization

00.10.2

0.4

0.6

1.0

Enalapril1117 events (26.5%)

Sac/Val914 events (21.8%)

1260

Cum

ulat

ive

Pro

babi

lity

41874212

36633579

22572123

15441488

896853

360 720 1080

0.3

0.5

39223883

30182922

249236

HR 0.80 (95% CI, 0.73–0.87), p<0.001

Sac/Val(n=4187)

Enalapril(n=4212)

Hazard Ratio(95% CI)

p-Value

Primary endpoint

914(21.8%)

1117(26.5%)

0.80(0.73–0.87) <0.001

Cardiovascular death

558(13.3%)

693(16.5%)

0.80(0.71–0.89) <0.001

Hospitalization for heart failure

537(12.8%)

658(15.6%)

0.79(0.71–0.89) <0.001

Sac/Val = Sacubitril/Valsartan.

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

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

All PatientsAge

<65 years≥65 years

SexMaleFemale

NYHA ClassI or IIIII or IV

Estimated GFR<60 mL/min/1.73 m2

≥60 mL/min/1.73 m2

Ejection fraction≤35%>35%

NT-proBNP≤Median>Median

HypertensionNoYes

Prior use of ACE inhibitorNoYes

Prior use of aldosterone antagonistNoYes

Prior hospitalization for heart failureNoYes

Death from Cardiovascular Causes

1.70.3

Sac/Val Better

Primary EndpointHazard Ratio

(95% CI)p-Value forInteraction

Hazard Ratio(95% CI)

p-Value forInteractionNo.

Sac/Val Enalapril

1.51.31.10.90.70.5

Enalapril Better

1.70.3

Sac/Val Better

1.51.31.10.90.70.5

Enalapril Better

4212

21682044

3259953

31301076

15202692

3722489

21162087

12412971

9463266

18122400

15452667

4187

21112076

3308879

31871002

15412646

3715472

20792103

12182969

9213266

19162271

15802607

0.47

0.63

0.03

0.91

0.36

0.16

0.87

0.09

0.10

0.10

0.70

0.92

0.76

0.73

0.36

0.33

0.14

0.06

0.32

0.19

Subgroup

Sac/Val(n=4187)

Enalapril(n=4212)

p-Value

Prospectively identified adverse eventsSymptomatic 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% 0.03Discontinuation 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.

PARADIGM-HF: Adverse Events

New FDA-Approved Sacubitril/Valsartan

Sacubitril/Valsartan

Brand name Entresto

IndicationThe fixed-dose combination of the neprilysin inhibitor sacubitril and the ARB valsartan is indicated to reduce the risk of CV death and HF hospitalization in patients with HF with reduced ejection fraction.

Dosage Start with 49/51 mg twice daily. Double the dose after 2–4 weeks as tolerated to maintenance dose of 97/103 mg twice daily.

Renal/hepatic impairment

For patients not currently taking an ACEI or ARB, or for those with severe renal impairment (eGFR <30 mL/min/1.73 m2) or moderate hepatic impairment, start with 24/26 mg twice daily.

Switching from an ACE inhibitor Stop ACE inhibitor for 36 hours before starting treatment.

ContraindicationsHistory of angioedema related to previous ACE inhibitor or ARB, concomitant use of ACE inhibitors, concomitant use of aliskiren in patients with diabetes. WARNING – pregnancy, hyperkalemia.

Side effects Hypotension, hyperkalemia, cough, dizziness, renal failure, and 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

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

SA node

SHIFT Study: Primary Endpoint of CV Death or Hospitalization for Worsening HF

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

0 12 18 24 30

40

10

0

Months

20

30

6

Ivabradine (n=3241)

Placebo (n=3264)P

atie

nts

with

Prim

ary

End

poin

t (%

)−18%

Placebo937 events (29%)

Ivabradine793 events (24%)

HR 0.82 (95% CI, 0.75–0.90) p<0.0001

ARR = 5%, NNT = 20

SHIFT Study: Effect of Ivabradine on Outcomes

Endpoint Ivabradine(n=3241)

Placebo(n=3264) HR p-Value

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 hospitalization for non-fatal MI

25% 30% 0.82 <0.0001

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

New FDA-Approved IvabradineIvabradine

Brand name Corlanor

Indication

To reduce the risk of hospitalization for worsening HF in patients with stable, symptomatic chronic HF with LVEF ≤ 35% who are in sinus rhythm with resting HR ≥70 bpm and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use.

Dosage

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 defects or in whom bradycardia could lead to hemodynamic compromise, start with 2.5 mg twice daily.

Contraindications

Acute decompensated HF; BP <90/50 mmHg; sick sinus syndrome or third-degree AV block, unless a functioning demand pacemaker is present; resting HR <60 bpm prior to treatment; severe hepatic impairment; pacemaker dependence. WARNING – fetal toxicity.

Side effects Occurring in ≥1% of patients are bradycardia, hypertension, atrial 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

HFrEF Stage CNYHA Class I – IV

Treatment:

For NYHA class II-IV patients. Provided estimated creatinine

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

For persistently symptomatic African Americans, NYHA class III-IV

Class I, LOE AACEI or ARB AND

Beta Blocker

Class I, LOE CLoop Diuretics

Class I, LOE AHydral-Nitrates

Class I, LOE AAldosterone Antagonist

AddAdd Add

For all volume overload, NYHA class II-IV patients

? Valsartan/Sacubutril? Ivabradine

Strategies:Disease ManagementRemote PA monitoringProcess ImprovementPatient EducationFrailty AssessmentPalliative CareGenetic Counseling

New Guidelines Have Emerged- 2016

COR/LOE 2016

RAASi in Heart Failure and Post-MI LV Dysfunction

Post-MILow EF

Mild-Mod CHFLow EF

CHFSevere HF

CHFPreserved EF

ACEi1 AIRESAVE

SOLVD CONSENSUS PEP-CHF(perindopril)

MRA EPHESUS1

(eplerenone)EMPHASIS1

(eplerenone)RALES1

(spironolactone)TOPCAT2

(spironolactone)

ARB1 OPTIMAALVALIANT

ELITE-IIHEALL

VAL-HeFTCHARM

CHARM-Preserved

I-PRESERVE

ARNI3 PARADIGM-HF(LCZ-696)

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.

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.

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 2013Classification Ejection

FractionDescription

I. Heart Failure with Reduced Ejection Fraction (HFrEF)

≤40% Also referred to as systolic HF. Randomized clinical trials have mainly enrolled patients with HFrEF and it is only in these patients that efficacious therapies have been demonstrated to date.

II. Heart Failure with Preserved Ejection Fraction (HFpEF)

≥50% Also referred to as diastolic HF. Several different criteria have been used to further define HFpEF. The diagnosis of HFpEF is 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

Date of download: 7/11/2016

Copyright © 2016 American Medical Association. All rights reserved.

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

Kaplan-Meier Curves, Adjusted for Age and Sex, Across the 3 Heart Failure GroupsThe stratified log-rank χ22 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.

Figure Legend:

A new HF phenotype 2016

Date of download: 7/11/2016 Copyright © 2016 American Medical Association. All rights reserved.

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

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

Table Title:

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?

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©2013, American Heart Association 39

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More Questions about Get With The Guidelines?

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Phone 214-706-1528