1

Updates in Heart Failure (HF) 2016:

ACC / AHA and ESC

Patrick McBride, MD, MPH

Professor of Medicine & Family Medicine, UW

School of Medicine and Public Health

Special thanks to:

Clyde W. Yancy, MD, MSc

Professor of Medicine, Chief, Cardiology

Northwestern University, Deputy Editor, JAMA Cardiology

Patrick E. McBride, MD, MPH

Professor of Medicine and Family Medicine

Associate Director, Preventive Cardiology

Interim, Associate Dean for Faculty Affairs

Senior Research Director, Research Networks

ICTR

I have no conflicts of interest to disclose

2

Objectives:The diagnosis and treatment of

HFrEF*

New Epidemiology 2016

•Prevention

•New Guidelines

•New Therapies

•New Phenotype

*HFrEF = heart failure reduced ejection

fraction

Copyright © 2016 American Medical Association. All rights reserved.

From: A Contemporary Appraisal of the Heart Failure Epide mic 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:

3

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.

Stages, Phenotypes and Treatment of HF

4

The treatment of HFrEF;

2016- Update

New Epidemiology

•Prevention

•New Guidelines

•New Therapies

•New Phenotype

Survival (years)

Ammar et al. Circulation 2007; 115:1563

Prevalence and prognostic significance of HF Stages

5

Comparison of short-term vs lifetime cumulative risks of CHF for men and

women at selected index ages

FRAMINGHAM Donald M. Lloyd-Jones et al Circulation 2002;106:3068

ONE IN FIVE INDIVIDUALS WILL DEVELOP HF

Lifetime risk for HF; indexed to blood pressure & sex

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STAGE A HF:

Hypertension as a Risk Factor for HF in African Ame ricans

Bibbins-Domingo et al. N Engl J Med. 360(12):1179-1190

Incidence of heart failure in young Americans

Bibbins-Domingo et al. New England Journal of Medicine. 360(12):1179-1190

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SPRINT Hypertension Trial

• Study Design: Randomized Single Blind

Primary Outcome Measures: First occurrence of a

myocardial infarction (MI), acute coronary

syndrome (ACS), stroke, heart failure (HF), or CVD

death [ Time Frame: 6 years ]

Secondary Outcome Measures: All-cause mortality ;

Development of end stage renal disease (ESRD),

Dementia, Decline in cognitive function, Small

vessel cerebral ischemic disease

• Estimated Enrollment: 9250

Increased CV risk as defined by SPRINT:

•clinical or subclinical cardiovascular disease other than stroke;

•chronic kidney disease, excluding polycystic kidney disease, with an estimated glomerularfiltration rate (eGFR) of 20 to less than 60 ml per minute per 1.73 m 2 of body-surface area, calculated with the use of the four-variable Modification of Diet in Renal Disease equation;

• a 10-year risk of cardiovascular disease of 15% or greater on the basis of the Framingham risk score;

•or an age of 75 years or older

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Systolic Blood Pressure in the Two Treatment Groups over the Course of the Trial

The SPRINT Research Group. N Engl J Med 2015;373:21 03-2116

Primary Outcome and Death from Any Cause

The SPRINT Research Group. N Engl J Med 2015;373:2103-2116

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Primary and Secondary Outcomes and Renal Outcomes

TheSPRINT Research Group. N Engl J Med 2015;373:2103 -2116

38%RR

The diagnosis and treatmentof HFrEF

•New Epidemiology

•Prevention

New Guidelines

•New Therapies

•New Phenotype

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Stages, Phenotypes and Treatment of HF

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

Pharmacologic Treatment for Stage C HFrEF

Yancy, C et al. JACC 2013

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New Guidelines Have Emerged- 2016

RAASi in Heart Failure and Post-MI LV Dysfunction

Post-MI

Low EF

Mild-Mod CHF

Low EF

CHF

Severe HF

CHF

Preserved EF

ACEi1 AIRE

SAVE

SOLVD CONSENSUS PEP-CHF

(perindopril)

MRAEPHESUS1

(eplerenone)

EMPHASIS1

(eplerenone)

RALES1

(spironolactone)

TOPCAT2

(spironolactone)

ARB1 OPTIMAAL

VALIANT

ELITE-II

HEALL

VAL-HeFT

CHARM

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.

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RAAS inhibition- 2016

ACE-I & ARB - 2016

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ARNI 2016

ARNI – (Harm) 2016

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Ivabradine 2016

ESC HF Guidelines 2016

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ESC HFrEF Treatment Algorithm

The treatment of HFrEF: 2016 - Update

•New Epidemiology•Prevention•New Guidelines

New Therapies•New Phenotype

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Endogenousvasoactive peptides

(natriuretic peptides, adrenomedullin,bradykinin, substance P,

calcitonin gene-related peptide)

Inactive metabolites

Neurohormonal activation

Vascular tone

Cardiac fibrosis, hypertrophy

Na+ 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

0

0.1

0.2

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

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Sac/Val(n=4187)

Enalapril(n=4212)

Hazard Ratio(95% CI)

p-Value

Primary endpoint914

(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

18

Sac/Val(n=4187)

Enalapril(n=4212)

p-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.

PARADIGM-HF: Adverse Events

New FDA-Approved Sacubitril / Valsartan

Sacubitril/ValsartanBrand name Entresto

Indication

The fixed-dose combination of the neprilysin inhibi tor sacubitriland the ARB valsartan is indicated to reduce the ri sk of CV death and HF hospitalization in patients with HF with red uced ejection fraction.

DosageStart with 49/51 mg twice daily. Double the dose af ter 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, o r for those with severe renal impairment (eGFR <30 mL/min/1.73 m2) or moderate hepatic impairment, start with 24/26 mg tw ice daily.

Switching from an ACE inhibitor

Stop ACE inhibitor for 36 hours before starting tre atment.

ContraindicationsHistory of angioedema related to previous ACE inhib itor or ARB, concomitant use of ACE inhibitors, concomitant use of aliskiren in patients with diabetes. WARNING – pregnancy, hype rkalemia.

Side effectsHypotension, hyperkalemia, cough, dizziness, renal failure, and angioedema (0.5% Sac/Val vs. 0.2% Enalapril).

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

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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 up-titrate 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 elevated HR

• 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 .

SA node

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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)

Pat

ient

s w

ithP

rimar

y E

ndpo

int (

%) −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

EndpointIvabradine(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 .

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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 treat ment, adjust dose based on HR. Max is 7.5 mg twice daily. In pat ients with conduction defects or in whom bradycardia could lea d to hemodynamic compromise, start with 2.5 mg twice dai ly.

Contraindications

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

Side effectsOccurring in ≥1% of patients are bradycardia, hypertension, atria l fibrillation, and luminous phenomena (phosphenes).

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

Practical 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

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Pharmacologic Treatment for Stage C HFrEF

? Valsartan/Sacubutril? Ivabradine

Strategies:Disease ManagementRemote PA monitoringProcess ImprovementPatient EducationFrailty AssessmentPalliative CareGenetic Counseling

Date of download: 7/11/2016Copyright © 2016 American Medical

Association. All rights reserved.

From: Potential Mortality Reduction With Optimal Implemen tation 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:

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The treatment of HFrEF:2016 - Update

•New Epidemiology

•Prevention

•New Guidelines

•New Therapies

New Classification

A new classification?

ESC HF GUIDELINES 2016

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Definition of Heart Failure -ACC/AHA 2013

Classification Ejection Fraction

Description

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

Taking the failure out of HF - 2016

• ***We can prevent the progression of HF

− Greater use of – PREVENTION, DIAGNOSIS, imaging, prognosis

& treatment ; early introduction of RAAS inhibitors

• Quality Improvement

− Still with untapped effectiveness – MAXIMIZE THERAPY!

− Device therapy (ICD/CRT) as indicated

• New drug therapies-

− ARNI (Sacubitril / Valsartan); Ivabradine

• Personalized Therapy driven by Pharmacogenomics

• - Future?

− Stem cells

− Gene Transfer; Growth Factors, Gene Editing

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Thank You!

Date of download: 7/11/2016Copyright © 2016 American Medical

Association. All rights reserved.

From: Characteristics and Outcomes of Adult Outpatients W ith 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: