the management of heart failure...the management of heart failure a practical but guideline-directed...

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1 spotlight.heart.org

The Management of Heart Failure

A Practical But Guideline-Directed Approach

Objectives Summarize approaches to diagnosis and classification of heart failure

Identify lifestyle changes necessary for patients with a diagnosis of heart failure

Explain how severity of heart failure is determined

Summarize approaches to treatment of heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF)

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Making the Diagnosis of Heart Failure

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Definition of Heart Failure A clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood

2013 ACCF/AHA Guideline for the Management of Heart Failure. Yancy CW, et al. Circulation. 2013;128:e240-e327. 4

Image Source: Jessup M, Brozena SA. New Engl J Med. 2003; 348:2007-2018:

HF with Reduced Ejection Fraction (HFrEF)

Normal Heart HF with Preserved Ejection Fraction (HFpEF)

HFrEF vs. HFpEF Classification EF (%) Description HFrEF ≤40 Also referred to as systolic HF. RCTs have mainly enrolled patients with

HFrEF; to date, only in these patients have effective therapies been demonstrated.

HFpEF ≥50 Also referred to as diastolic HF. Several different criteria have been used to further define HFpEF. Diagnosis of HFpEF is challenging because it largely involves excluding other potential noncardiac causes of symptoms suggestive of HF. To date, no effective therapies have been identified.

HFpEF, borderline

41 – 49 These patients fall into a borderline or intermediate group. Their characteristics, treatment patterns, and outcomes appear similar to those of patient with HFpEF.

HFpEF, improved >40 It is now recognized that a subset of patients with HFpEF previously had HFrEF. 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.

2013 ACCF/AHA Guideline for the Management of Heart Failure. Yancy CW, et al. Circulation. 2013;128:e240-e327.

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Causes of HF

o  May result from disorders of pericardium, endocardium, heart valves, great vessels, or metabolic abnormalities

o  All potential causes must be evaluated, with consideration of multigenerational family histories and genetic testing

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Diagnosis of HF

Cardinal manifestations o  Dyspnea and fatigue ▪  Exercise intolerance

o  Fluid retention ▪  Pulmonary and/or

splanchnic congestion

▪  Peripheral edema

Physical findings o  Elevated central venous

pressure o  Bibasilar crackles (rales) o  S3, S4 gallop o  Bilateral lower extremity

edema

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Diagnostic Tests ✓  Complete blood count ✓  Urinalysis ✓  Comprehensive metabolic profile ✓  Thyroid stimulating hormone ✓  Chest x-ray

▪  Pulmonary venous congestion and cardiomegaly are strongly associated with the likelihood of clinical heart failure.

✓  12-lead ECG: perform initially on all patients presenting with HF symptoms

✓  Echocardiography or MRI to assess ventricular function ✓  Non-invasive assessment of ischemia

▪  Recommended if risk factors are positive and angina is present, to determine extent of ischemic burden

2013 ACCF/AHA Guideline for the Management of Heart Failure. Yancy CW, et al. Circulation. 2013;128:e240-e327.Wang CS, et al. JAMA. 2005;19;294:1944-5 8

BNP & NT-proBNP Biomarkers

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Causes of Elevated BNP/NT-proBNP* Cardiac Noncardiac •  HF, including RV syndromes •  Acute coronary syndrome •  Heart muscle disease, including

LVH •  Valvular heart disease •  Pericardial disease •  Atrial fibrillation •  Myocarditis •  Cardiac surgery •  Cardioversion

•  Advancing age •  Anemia •  Renal failure •  Pulmonary causes: obstructive

sleep apnea, severe pneumonia, pulmonary hypertension

•  Critical illness •  Bacterial sepsis •  Severe burns •  Toxic-metabolic insults, including

cancer chemotherapy and envenomation

*Obesity can decrease levels

Illustration from Swedberg, K. Nat. Rev. Cardiol. 2015 ;12:73-5. Used with permission. 2013 ACCF/AHA Guideline for the Management of Heart Failure. Yancy CW, et al. Circulation. 2013;128:e240-e327.

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Evaluation of Dyspnea Patient presents with

dyspnea

Take medical history, perform physical examination, (+/-) ECG, thoracic radiography;

determine BNP or NT-proBNP

BNP<100 pg/mL or NT-proBNP< 300pg/mL

HF highly unlikely (< 2%)

BNP or NT-proBNP between 2 cutoff points

HF unlikely; run additional tests

BNP > 300 pg/mL or NT-proBNP > 500 pg/mL

HF highly likely

Adapted with permission from Maisel A. Crit Pathways Cardiol J Evidence-Based Med. 2002;1:67-73. 10

Assessing Classification and Severity of Heart Failure

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HF Severity: ACC/AHA Stages and NYHA Functional Classification

Increasing Severity

NYHAFunc*onalClassifica*on

ACCF/AHAStages

Class I • No limitation of

physical activity • Ordinary physical

activity does not cause symptoms of HF

Class II • Slight limitation of

physical activity • Comfortable at rest • Ordinary activity

results in symptoms of HF

Class III • Marked limitation of

physical activity • Comfortable at rest • Less than ordinary

activity results in symptoms of HF

Class IV • Unable to carry on

any physical activity without symptoms of HF, or symptoms of HF at rest

Class IIIa • No dyspnea at rest

Class IIIb • Recent dyspnea at rest

Stage A • High risk for

developing HF • No structural disease

of the heart • No symptoms of HF

Stage B • Structural disease • No symptoms of HF

Stage D • Refractory HF • Requires specialized

treatment strategies

Stage C • Structural disease • Past or current

symptoms of HF

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Modified from 2013 ACCF/AHA Guideline for the Management of Heart Failure. Yancy CW, et al. Circulation. 2013;128:e240-e327.

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Figure from Ammar AA, et al. Circulation. 2007;115:1563-70. Used with permission.

Survival (years)

Surv

iving

Prevalence and Prognostic Significance of HF Stages

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Log-rank P <0.0001

Predischarge BNP: Predictor of Postdischarge Events

Figure from Logeart D, et al. J Am Coll Cardiol. 2004;43:635-41. Used with permission. 14

P <0.0001

P <0.0001

Complexity of Heart Failure Management

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Complexities of HF Care

16 Albert NM, et al. Circulation Heart Fail. 2015;8:384-409.

eg, Patients with: •  Known structural heart disease • HF signs and symptoms

Stages and Treatment of HF Stage A Stage B Stage C Stage D

THERAPYGoals• Heart-healthy lifestyle•  Prevent vascular

coronary disease•  Prevent LV structural

abnormalitiesDrugs•  ACEI or ARB in

appropriate patients for vascular diseases or DM

•  Statins as appropriate

eg, Patients with:•  Previous MI•  LV remodeling including LVH and low EF

•  Asymptomatic valvular disease

THERAPYGoals•  Prevent HF symptoms•  Prevent further

cardiac remodelingDrugs•  ACEI or ARB as

appropriate•  Beta blockers as

appropriateIn selected patients:•  ICD• Revascularization or

valvular surgery as appropriate

eg, Patients with:•  HTN•  Atherosclerosis•  DM•  Obesity•  Metabolic syndrome

orPatients •  Using cardiotoxins•  w/family history of

cardiomyopathy

Structural heart disease

HFpEF

HFrEF

eg, Patients with:• Marked HF symptoms

at rest• Recurrent

hospitalizations despite GDMT

Develop-ment of symptoms of HF

Refractory symptoms of HF at rest, despiteGDMT

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, eg, HTN, AF, CAD, DM

THERAPYGoals• Control symptoms•  Improve HRQOL• Reduce hospital

readmissions•  Establish patient’s end-

of-life goalsOptions: •  Advanced care

measures• Heart transplant• Chronic inotropes•  Temporary or

permanent MCS•  Experimental surgery or

drugs•  Palliative care and

hospice•  ICD deactivation


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 In selected patients • Hydralazine/ isosorbide dinitrate

•  ACEI and ARB • Digitalis • CRT •  ICD • Revascularization or valvular surgery as appropriate

Social Support in HF

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Sodium and Water Restriction in HF

Sodium Restriction o  Discussions should be patient-

centered o  When considered appropriate, sodium

restriction is a Class IIa recommendation

o  Sodium restriction is reasonable for some patients with symptomatic HF to reduce congestive symptoms. (Level of Evidence: C)

o  More data are needed to determine the correct threshold of sodium restriction

Water restriction o  Should be considered but not

needed for all patients; Class IIa recommendation

o  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) ▪  Arginine vasopressin antagonists

may also be indicated for volume overload states associated with profound hyponatremia


Sleep Disorders, Sleep Apnea, and HF •  Sleep-disordered breathing is common in patients with

HFrEF; reported prevalence rates are 50%-75%.•  Obstructive sleep apnea occurs more often in HF patients

than in the general population.•  Central sleep apnea, which may manifest as Cheyne–Stokes

respiration, is found in 25 to 40% of patients with HFrEF.•  The prevalence of central sleep apnea increases in parallel

with increasing severity of HF and worsening cardiac dysfunction.

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Cowie MR, et al. N Engl J Med. 2015;373:1095-105Oldenburg O, et al. Eur J Heart Fail 2007; 9:251-257.

Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic HF: The SERVE-HF Trial

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All-cause mortality and cardiovascular mortality were significantly higher in the adaptive servo-ventilation group than in the control group.

Figures from Cowie MR et al. N Engl J Med. 2015;373:1095-105. Permission to use.

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Weight Management in Heart Failure

2013 ACCF/AHA Guideline for the Management of Heart Failure. Yancy CW, et al. Circulation. 2013;128:e240-e327. Habbu A, Lakkis NM, Dokainish . Am J Cardiol. 2006;98:944-8.

Body Mass Index

Mor

talit

y

Cardiac Cachexia Morbidly Obese Normal/Overweight/Obese

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Alcohol Consumption in HF o  Light-to-moderate alcohol consumption appears to be safe in patients with LV

systolic dysfunction ▪  The AHA considers moderate alcohol consumption to be an average of 1-2 drinks/day for men

and 1 drink/day for women. o  There is insufficient evidence to recommend the use of alcohol to patients with LV

dysfunction who do not currently drink alcohol o  Heavy alcohol consumption should be discouraged in all patients with HF and is

especially important for patients with LV systolic dysfunction

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Infographic from the National Institute on Alcohol Abuse and Alcoholism. Cooper HA, et al J Am Coll Cardiol. 2000;35:1753-9.Djoussé L, Gaziano JM. Curr Atheroscler Rep. 2008 Apr;10:117-20.

Harmful Drugs in HF (Class III) o  NSAIDs o  Decongestants

▪  eg, pseudoephedrine o  Thiazolidinediones o  Antiarrhythmics

▪  Exceptions: amiodarone, dofetilide

(Level of Evidence: B) o  Infused positive inotropes

▪  Exceptions: patients awaiting heart transplantation, patients needing palliative care)

(Level of Evidence: C) 2013 ACCF/AHA Guideline for the Management of Heart Failure. Yancy CW, et al. Circulation. 2013;128:e240-e327. Chua SS, et al. Br J Clin. Pharmac. 1989;28:369-372. 24

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Drugs of Unproven Value in HFrEF (Class III)

•  Nutritional supplements (Level of Evidence: B)

•  Hormonal therapies (Level of Evidence: C)

•  Calcium channel blockers (except amlodipine) (Level of Evidence: A)

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2013 ACCF/AHA Guideline for the Management of Heart Failure. Yancy CW, et al. Circulation. 2013;128:e240-e327. .

Exercise in HF o Class I

Exercise training (or regular physical activity) is recommended as safe and effective for patients with HF who are able to participate to improve functional status.

(Level of Evidence: A)

o Class IIa Cardiac rehabilitation can be useful in clinically stable patients

with HF to improve functional capacity, exercise duration, HRQOL, and mortality.

(Level of Evidence: B)

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Cardiac Rehabilitation in HF o  Approved by CMS in February 2014 o  Stable chronic HF defined as

▪  LVEF ≤ 35%

▪  NYHA class II-IV symptoms despite optimal therapy for ≥ 6 weeks

▪  No recent CV hospitalizations or procedures for ≤6 weeks

▪  No planned CV hospitalizations or procedures for ≤6 months

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CMS.February 2014. https://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=270.

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Management of HF

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Management of HFrEF

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Plan treatment strategy

HFrEF

Guideline Directed Medical Therapy

HFpEF

Treatment directed at signs and symptoms,

hemodynamics, etiology

Assess etiology


Yancyetal.2017ACC/AHA/HFSAfocusedupdatetothe2013ACCF/AHAguidelineforthemanagementofheartfailure:areportoftheAmericanCollegeofCardiology/AmericanHeartAssociaBonTaskForceonClinicalPracBceGuidelinesandtheHeartFailureSocietyofAmerica.CirculaBon.2017

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Cardiovascular Regulation by SNS, RAAS, ANP and Local Mediators

Adapted from Corti C, et al. Circulation. 2001;104:1856-1862. Used with permission. 31

Copyright © American Heart Association, Inc. All rights reserved.

Mortality Benefit Using ACEIs in HFrEF

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Study (N)

Drug

HF Severity Class

Target Dose

Average Dose

Outcomes

Chronic HF CONSENSUS (N=253)1

Enalapril IV 20 mg BID 18.4 mg ↓31% mortality, P=0.001

SOLVD (N=2569)2

Enalapril I-IV 10 mg BID 16.6 mg ↓16% mortality, P=0.0036

ATLAS (N=3164)3

Lisinopril II-IV 35 mg/d (high dose)

32.5-35 mg (high dose)

↓12% all-cause mortality and hospitalizations, P=0.002 (high dose)

Post-MI LVD SAVE (N=2231)4

Captopril Post MI LVD, EF ≤ 40%

50 mg TID NR* ↓19% mortality, P=0.019

AIRE (N=2006) 5

Ramipril Post MI LVD 5 mg BID NR ↓27% mortality, P=0.002

TRACE (N=1749)6

Trandolapril Post MI LVD, EF ≤35%

4 mg daily NR ↓22% mortality, P=0.001

1. CONSENSUS Trial Study Group. New Engl J Med. 1987;316:1429-35.; 2. SOLVD Investigators. New Engl J Med.1991; 325:293-302.; 3. ATLAS Study Group. Circulation 1999;100:2312-8; 4. SAVE Study Group. New Engl J Med. 1992;327:669-77.; 5. AIRE Investigators. Lancet 1993;342:821-8.; 6. TRACE Study Group. New Engl J Med. 1995;333:1670-6.

*NR=Not reported

Target Dosing for ACEIs/ARBs in HFrEF Drug Class; Drug Initial Dose(s) Maximum Dose(s) Mean Doses Achieved in Clinical Trials ACEIs Captopril 6.25 mg TID 50 mg TID 122.7 mg/day Enalapril 2.5 mg BID 10 to 20 mg BID 16.6 mg/day Lisinopril 2.5 to 5 mg QD 20 to 40 mg QD 32.5 to 35.0 mg/day Fosinopril 5 to 10 mg QD 40 mg QD N/A Perindopril 2 mg QD 8 to 16 mg QD N/A Quinapril 5 mg BID 20 mg BID N/A Ramipril 1.25 to 2.5 mg QD 10 mg QD N/A Trandolapril 1 mg QD 4 mg QD N/A ARBs Candesartan 4 to 8 mg QD 32 mg QD 24 mg/day Losartan 25 to 50 mg QD 50 to 150 mg QD 129 mg/day Valsartan 20 to 40 mg BID 160 mg BID 254 mg/day


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Practical Points For Use of ACEIs and ARBs in HF o  Initiate at low doses, then titrate to doses used in clinical trials, as tolerated o  Use together with a beta blocker unless there is a contraindication o  Prescribe with caution in patients with low blood pressure (SBP <80 mmHg), markedly increased serum creatinine (>3 mg/dL),

decreased serum Na+ (<130 mg/dL), or elevated serum K+ (>5 mEq/L) o  ARBs

▪  Add to ACEI if symptomatic and aldosterone antagonist is not indicated or tolerated ▪  Avoid routine combined use of ACEI + ARB + aldosterone antagonist

o  Intolerance ▪  Cough: substitute with an ARB ▪  Angioedema: avoid ACEI, consider ARB (with caution) ▪  Hyperkalemia or renal insufficiency: consider hydralazine and oral nitrate (Class IIa, LOE B)

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2013 ACCF/AHA Guideline for the Management of Heart Failure. Yancy CW, et al. Circulation. 2013;128:e240-e327

Effects of BBs on Mortality Reduction in HFrEF

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Study (N)

Drug

HF Severity Class

Target Dose

Average Dose

Outcome

US Carvedilol (N=366)1

Carvedilol II/III 6.25 -25 mg BID

NR* ↓48% in disease progression, P=0.007

CIBIS-II (N=2647)2

Bisoprolol III/IV 10 mg daily 7.8 mg/d ↓34% in mortality, P<0.0001

MERIT-HF (N=3991)3

Metoprolol succinate

II-IV 200 mg daily 159 mg/d ↓34% in mortality, P=0.0062 (adjusted)

COPERNICUS (N=2289)4

Carvedilol IV, EF <25% 25 mg BID 18.5 mg BID ↓35% in mortality, P=0.0014 (adjusted)

CAPRICORN (N=1959)5

Carvedilol Post-MI LVD, EF ≤ 40%

25 mg BID 20.2 mg BID ↓23% mortality, P=0.031

COMET

(N=1511)6 Carvedilol vs. metoprolol tartrate

II-IV Carvedilol: 25 mg BID Metoprolol: 50 mg BID

Carvedilol: 41.8 mg/d Metoprolol: 85 mg/d

↓17% in mortality with carvedilol vs metoprolol, P=0.0017

1. Colucci WS et al. Circulation 1996;94:2800-6.; 2. CIBIS II Investigators. Lancet 1999;353:9-13.; 3. MERIT-HF Study Group. Lancet 1999;353:2001-7.; 4. Packer M et al. New Engl J Med. 2001;344:1651-8.; 5. Dargie HJ. Lancet 2001;357:1385-90.; 6. Poole-Wilson PA, et al. Lancet 2003;362:7-13.

NR: not reported

1. Figure from MERIT-HF Study Group. Lancet. 1999;353:2001-2007. Used with permission. 2. Figure modified from CIBIS-II Investigators. Lancet. 1999;353:9-13. Used with permission. 3. Figure from Packer M et al. New Engl J Med. 2001;344:1651--1658. Used with permission.

Mortality Benefit Using Beta Blockers in HFrEF

0 4 8 12 16 20 24 28

Time (Days)

CIBIS -II2

P<0.0001

Bisoprolol

Placebo

N=2647

0 200 400 600 800

Surv

ival (

%)

COPERNICUS3

Surv

ival (

%)

34% 35%

Carvedilol

Placebo

P=0.00013 (unadjusted)P=0.0014 (adjusted)

100

90

80

70

60

50

N=2289

Months

80

60

40

20

100

0

Follow--up: (Months)

34% Mortality:

MERIT- HF1

Cum

ulat

ive m

orta

lity (

%) 20

15

10

5

0

P=0.0062 (adjusted)P=0.00009 (nominal)

Placebo

N=3991

0 3 6 9 12 15 18 21

ER Metoprolol Succinate

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Practical Points For Use of BBs in HF o  Use one of the three evidence-based BBs proven to reduce mortality

▪  Initiate at low doses, then titrate up to doses used in clinical trials, as tolerated

o  Use together with an ACEI unless there is a contraindication o  Initiate after optimizing fluid status, off inotropic therapy o  Use with caution in patients with reactive airway disease or asymptomatic

bradycardia if those symptoms persist

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Drug Initial Daily Dose(s) Maximum Daily Dose(s)

Mean Doses Achieved in Clinical Trials

Bisoprolol 1.25 mg once 10 mg once 8.6 mg/day Carvedilol 3.125 mg twice 50 mg twice 37 mg/day Carvedilol CR 10 mg once 80 mg once N/A Metoprolol succinate CR/XL 12.5 to 25 mg once 200 mg once 159 mg/day

2013 ACCF/AHA Guideline for the Management of Heart Failure. Yancy CW, et al. Circulation. 2013;128:e240-e327

Effects of Aldosterone Receptor Antagonists on Mortality Reduction in HFrEF

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Study (N)

Drug

HF Severity Class

Target Dose

Average Dose

Outcomes

RALES (N=1663)1

Spironolactone III/IV 25 or 50 mg daily

26 mg/day ↓30% in mortality, P<0.001

EPHESUS (N=6632)2

Eplerenone Post-MI LVD, EF ≤40%

50 mg daily 42.6 mg/day

↓15% in mortality, P=0.008

EMPHASIS-HF

(N=2737)3 Eplerenone II, EF ≤35% 50 mg daily 39.1 mg/d ↓24% in mortality, P=0.008

1. Pitt B, et al. N Eng J Med. 1999; 341:709-17.2. Pitt B, et al. N Eng J Med 2003; 348:1309-21.3. Zannad F, et al. N Eng J Med 2011; 364:11-21.

*NR: not reported

Practical Points For Use of Aldosterone Receptor Antagonists in HF

o  Initiation and maintenance dose ▪  Spironolactone 12.5 to 25 mg once daily, increasing to up to 25 mg twice

daily ▪  Eplerenone 25 mg once daily, increasing to 50 mg/day ▪  If marginal renal function, initiate with every-other-day dosing

o  Minimize the risk of hyperkalemia ▪  Use only if SCr <2.5 mg/dL or eGFR >30 mL/min/1.73m2 and/or K+ <5

mEq/L ▪  May need to discontinue K supplementation and/or reduce dietary K+

intake ▪  Monitor K+ levels and renal function

•  On days 3 and 7 after MRA treatment initiation •  At least monthly for first 3 months

39 2013 ACCF/AHA Guideline for the Management of Heart Failure. Yancy CW, et al. Circulation. 2013;128:e240-e327.

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Drugs that Reduce Mortality in HFrEF

-12 -16

-34 -30

-40

-30

-20

-10

0 Decrease in Mortality

40

Redu

c*on

inM

orta

lity(%

)

AngiotensinReceptorBlocker

AngiotensinConver*ngEnzyme

Inhibitor BetaBlocker

Mineralocor*coidReceptorAntagonist

Summary of Data from CHARM-LowEF,1 CIBIS II,2 EMPHASIS-HF,3 MERIT-HF,4 RALES,5 and SOLVD-Treatment6

1.  Young JB, et al. Circulation. 2004;110:2618-26. 2. CIBIS II Investigators. Lancet 1999;353:9-13.3.  Zannad F, et al. N Eng J Med 2011; 364:11-21;

4. MERIT-HF Study Group. Lancet 1999;353:2001-7. 5. Pitt B, et al. N Eng J Med. 1999; 341:709-176. SOLVD Investigators. New Engl J Med. 1991

Figure from Taylor A, et al. New Engl J Med. 2004;351:2049-57. Used with permission.

Mortality Benefit Using Hydralazine/ISDN in HFrEF: Results from A-HeFT*

43%Mortality

*Patients had NYHA III/IV HF, EF <35%, and were self-identified as African American.

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o  Titrate to target doses

o  Adherence can be poor due to large number of tablets needed, frequent side

effects o  Proven benefit in African Americans receiving optimal therapy with ACEI/BBs o  Useful if patient cannot receive ACEI/ARB due to intolerance

Hydralazine and ISDN Initial Daily Dose(s) Maximum Daily Dose(s) Mean Doses Achieved in Clinical Trials

Fixed-dose combination 37.5 mg hydralazine/20 mg ISDN 2 times daily

75 mg hydralazine/40 mg ISDN 3 times daily

~175 mg hydralazine/90 mg ISDN daily

Hydralazine and ISDN Hydralazine: 25 to 50 mg, 3 or 4 times daily Isosorbide dinitrate: 20 to 30 mg 3 or 4 times daily

Hydralazine: 300 mg daily in divided doses Isosorbide dinitrate: 120 mg daily in divided doses

N/A

Practical Points For Using Hydralazine/ISDN in HF


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Management of HFpEF

43

Plan treatment strategy

HFrEF

Guideline Directed Medical Therapy

HFpEF

Treatment directed at signs and symptoms,

hemodynamics, etiology

Assess etiology


Morbidity Benefit of ACEIs/ARBs in HFpEF

44

Study (N) Drug

HF Severity Class

Target Dose Outcome

CHARM-Preserved1 (N=3023)

Candesartan II-IV, EF>40% 32 mg No ∆ in CV death or HF hospitalization (P >0.05)

I-Preserved2 (N=4128)

Irbesartan II-IV, EF≥ 45%, >60y

300 mg No ∆ in death or CV hospitalization (P >0.05)

PEP-CHF3

(N=850) Perindopril II-IV, EF≥ 40%,

>70y 4 mg NS ∆ in death or HF hospitalization (P >0.05)

NS=nonsignificant

1.Yusuf S, et al. Lancet 2003;362:777-81.2. Massie BM, et al. NEJM 2008; 359:2546-67.3. Cleland JGF, et al. Eur Heart J 2006;27:2338-45.

•  Fewer total and fewer HF admissions at f/u (P <0.05)

•  ↓14% Non-fatal MI/non-fatal stroke (P <0.05)

•  ↓ 38% HF hospitalization, (P <0.05)

Mortality Benefit of BBs in HFpEF

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Study (N) Drug

HF Severity Class Target dose Outcome

BHAT (N=158)1

Propranolol or control

II-III, EF >40% after diuretics and ACEI for 2 mos

90 mg/day ↓Total mortality at 32 mo (56% vs. 76%, P = 0.007) ↓Combined endpoint of total mortality and non-fatal MI (59% vs. 82%, P=0.002)

SENIORS (N=2111; HFpEF n=752)2

Nebivolol Substudy of pts with EF ≥35% vs. EF <35%

10 mg/d NS ∆ in death or CV hospitalization in preserved EF group (P >0.05)

NS=nonsignificant

1. Aronow WS, et al. Am J Cardiol 1997;80:207-9.2. Van Veldhuisen DJ, et al. J Am Coll Cardiol. 2009;53:2150-8.

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Spironolactone in HFpEF Patients: TOPCAT Study

Figure from Pitt B, et al. New Engl J Med. 2014;370:1383-1392. Used with permission.

Spironolactone

HR=0.89 (0.77-1.04), p = 0.138

351/1723 (20.4%)

320/1722 (18.6%) Placebo

Primary Outcome: CV Death, HF Hospitalization, or Resuscitated Cardiac Arrest

Estim

ated

Cum

ulat

ive P

ropo

rtion

of P

atien

tswi

th P

rimar

y End

Poi

nt*

SpironolactonePlacebo

*Composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of HF.

New Therapies for the Management of HFrEF

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New Therapies: If Inhibitor Ivabradine

48 Illustration from Canet E, et al. Ann N Y Acad Sci. 2011;1222:90-99. Used with permission.

o  Selective blockade of HCN channels in a concentration-dependent manner

▪  Only works when channels are open

o  Selectively reduces heart rate o  No effect on ionotropy and

intracardiac conduction o  Net Effect:

▪  Reduces myocardial oxygen demand

▪  Prolongs diastole à increases myocardial perfusion and coronary flow

Sinus Node

Ivabadrine

Heart Rate Reduction

0 mV

-40 mV

-70 mV

If channel

Na+ Na+

K+

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SHIFT Study: Ivabradine Other Findings

o  Hospital admissions for worsening heart failure ▪  Ivabadrine 15.6% vs. placebo 20.2%; HR 0.74

(95% CI 0.66-0.83), P<0.0001 o  All-cause mortality

▪  Ivabradine 16% vs placebo 17%, P=0.092 o  In patients receiving at least 50% or more of

target beta-blocker doses: ▪  No significant benefit on primary endpoint (HR

0.90 [95% CI 0.72-1.04], P=0.155) ▪  Significant reductions in hospital admissions

due to worsening heart failure (HR 0.81 [95% CI 0.67-0.97], P=0.021)

49Figure from Swedberg K, et al. Lancet. 2010;376:875-85. Used with permission.

Primary Composite Endpoint: CV death and Hospitalization for Worsening HF *

Patie

nts w

ith P

rimar

y Com

posit

e End

poin

t (%

)

Placebo (937 events)Ivabradine (793 events)

HR: 0.82 (95% CI 0.75-0.90; P <0.0001

Time (months)

18%

Practical Points for Using Ivabradine in HF o  FDA-approved indication: Reduce the risk of hospitalization

for worsening HF in patients with stable, symptomatic chronic HF and EF ≤ 35%, SR with resting HR ≥ 70 bpm, and on maximally tolerated doses of BBs or have a contraindication to BB use

o  Do not use in patients with: ADHF or BP <90/50 mmHg, resting HR <60 bpm, pacemaker dependent, severe heart block, severe hepatic impairment

o  Watch use with CYP3A4 inhibitors o  Side effects: bradycardia, HTN, AF, and luminous

phenomena (phosphenes)

50 Corlanor Prescribing Information, April 2015.Swedberg K, et al. Lancet. 2010;376:875-85.

Dosing of Ivabradine in HF o  Start at 5 mg twice daily (2.5 mg if bradycardic or conduction

defects) o  After 2 weeks, adjust dose based on resting heart rate

51

Resting Heart Rate Dose Adjustment After 2 weeks >60 bpm Increase by 2.5 mg twice daily up to a

maximum of 7.5 mg twice daily 50-60 bpm Maintain dose <50 bpm or signs and symptoms of bradycardia

Decrease by 2.5 mg twice daily; if already at 2.5 mg twice daily, discontinue

Corlanor Prescribing Information, April 2015.Swedberg K, et al. Lancet. 2010;376:875-85.

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New Therapies: LCZ696 (Sacubitril/Valsartan) Dual Neurohormonal Antagonism

52

*Sacubatril inhibits the neutral endopeptidase neprilysin; valsartan blocks AT1 receptors.

Illustration from Swedberg, K. Nat. Rev. Cardiol. 2015 ;12:73-5. Used with permission.

53

PARADIGM-HF: HF Outcomes

Figures from McMurray JJ, et al. New Eng J Med. 2014;371:993-1004. Used with permission.

*CV death or HF hospitalization.

16%20%

Primary Endpoint* Death from Any Cause

Practical Points for Using LCZ696 (Sacubitril/Valsartan) in HF

o  FDA-approved indication: to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II–IV) and reduced EF

o  Dosing: ▪  Start with 49/51 mg (sacubitril/valsartan) twice daily; double to target dose of

97/103 mg twice daily after 2-4 wks, as tolerated ▪  For ACEI/ARB-naïve patients or those on low-dose ACEI/ARBs, severe renal

impairment, or moderate hepatic impairment •  Start with 24/26 mg twice daily; Increase to 49/51 mg twice daily after 2-4

wks, then double to achieve 97/103 mg twice daily as tolerated •  36-hour washout period required if switching from an ACEI to LCZ696

o  Boxed warning: Fetal toxicity; discontinue in pregnancy o  Side effects: hypotension, hyperkalemia, increased serum creatinine,

angioedema

Entresto Prescribing Information. Novartis Pharmaceuticals Corporation. August 2015..

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Iron Supplementation in HF: CONFIRM-HF Study

55 Ponikowski P, et al. Eur Heart J. 2015;36:657-68.

Time to 1st HF Hospitalization

HR 0.39 (95% CI 0.19–0.82), P = 0.009

61%



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Device Therapy for HF Treatment of Stages A to D

Mortality Benefit With ICD: SCD-HeFT Study

59Figure from Bardy GH, et al. New Engl J Med. 2005;352:225-37. Used with permission.

Mortality: 23%

Mortality/Morbidity Benefit With CRT

60

MADIT-CRT1

1. Figure from Moss AJ, et al. New Engl J Med .2009;361:1329-38. Used with permission.

2. Figure from Tang AS, et al. New Engl J Med. 2010;363:2385-95. Used with permission.

RAFT2

34% Mortality and 1st HF Event:

25% Death/Hospitalization for HF:

Mortality: 25%

DeathorHospitaliza*onforHF

Death

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Indications for CRT Therapy

61

2013 ACCF/AHA Guideline for the Management of Heart Failure. Yancy CW, et al. Circulation. 2013;128:e240–e327.

Patient with cardiomyopathy on GDMT for ≥ 3 mo or on GDMT and ≥40 d after MI, or with implantation or defibrillation device for special indications

LVEF≤35% Evaluategeneralhealthstatus

Acceptablenoncardiachealth

EvaluateNYHAclinicalstatus

ComorbidiBesand/orfrailtylimitsurvivalwithgood

funcBonalcapacityto<1y

ConBnueGDMTwithoutimplanted

device

NYHA Class I •  LVEF ≤30% •  QRS ≥150 ms •  LBBB pattern •  Ischemic

cardiomyopathy •  QRS ≤150 ms •  Non-LBBB pattern

NYHA Class II •  LVEF ≤35% •  QRS ≥150 ms •  LBBB pattern •  Sinus rhythm •  LVEF ≤35% •  QRS 120-149 ms •  LBBB pattern •  Sinus rhythm •  LVEF ≤35% •  QRS ≥150 ms •  Non-LBBB pattern •  Sinus rhythm •  QRS ≤150 ms •  Non-LBBB pattern

NYHA Class III and Ambulatory Class IV

•  LVEF ≤35% •  QRS ≥150 ms •  LBBB pattern •  Sinus rhythm •  LVEF ≤35% •  QRS 120-149 ms •  LBBB pattern •  Sinus rhythm •  LVEF ≤35% •  QRS ≥150 ms •  Non-LBBB pattern •  Sinus rhythm •  LVEF ≤35% •  QRS 120-149 ms •  Non-LBBB pattern •  Sinus rhythm

Special CRT Indications

•  Anticipated to require frequent ventricular pacing (>40%)

•  Atrial fibrillation, if ventricuar pacing is required and rate control will result in near 100% ventricular pacing with CRT

RecommendationClass I

Class IIa

Class IIb

Class III

Final Considerations and Conclusions

62

HF Management Considerations o  Don’t try to add too many new medications too fast

▪  HF medications were tested on ambulatory patients, not newly decompensated patients in the hospital

o  Don’t forget the basics before adding the newest “hot” drug ▪  Optimal medication dosing of current therapies, patient

education, and lifestyle management (including volume maintenance with diuretics)

▪  Coordination of care, team care, communication/collaboration among healthcare providers are essential!

o  Patients in clinical trials are often not patients in your office ▪  Most HF patients are elderly, half are women, and half have

HFpEF. 63

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Summary o  Heart failure can be treated and treated well, but be honest with

patients/families about stage and prognosis. o  It is important to discriminate between HFrEF and HFpEF. o  An array of evidence-based medical and device therapies are

available to improve outcomes and alleviate symptoms in HFrEF. o  Treatment for HFpEF remains under active study. o  Adjunctive steps including diet, exercise, and patient education are

very helpful. o  A team-based, collaborative approach is essential when patients

have comorbid conditions and multiple healthcare providers.

64

Thank You!

Back-up Slides

66

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Classification of Heart Failure ACCF/AHA Stages of HF NYHA Functional Classification

A At high risk for HF but without structural heart disease or symptoms of HF

None

B Structural heart disease but without signs or symptoms of HF

I No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF

C Structural heart disease with prior or current symptoms of HF

I No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF

II Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of HF

III Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of HF

IV Unable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest.

D Refractory HF requiring specialized interventions

IV Unable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest

67 Yancy CW, et al; ACCF/AHA Task Force on Practice Guidelines. Circulation.2013:128:e240-e327.

Januzzi J L , Troughton R. Circulation. 2013;127:500-508

Copyright © American Heart Association

Changes in N-terminal pro-BNP During 4-Month Follow-up Valsartan Heart Failure Trial

68

Recommendations for Biomarkers in HF Biomarker, Application Setting COR LOA

Natriuretic peptides

Diagnosis or exclusion of HF Ambulatory, Acute I A

Prognosis of HF Ambulatory, Acute I A

Achieve GDMT Ambulatory IIa B Guidance of acutely decompensated HF therapy Acute IIb C

Biomarkers of myocardial injury

Additive risk stratification Acute,

Ambulatory I A

Biomarkers of myocardial fibrosis

Additive risk stratification

Ambulatory IIb B

Acute IIb A


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Heart Failure: HFrEF Treatment o  Class IA: ACEI to reduce morbidity and mortality

▪  ARB in patients who are ACEI intolerant to reduce morbidity and mortality

o  Class IA: Beta blockers (bisoprolol, carvedilol, and SR metoprolol succinate) to reduce morbidity and mortality

o  Class IA: Aldosterone receptor antagonists in patients with NYHA class II-IV and who have LVEF <35% to reduce morbidity and mortality

o  Class IA: Hydralazine and isosorbide dinitrate (ISDN) for patients self-described as African Americans with NYHA III-IV HFrEF receiving optimal therapy with ACEI and BBs to reduce morbidity and mortality

o  Class IIaB: Digoxin to reduce hospitalizations for heart failure

o  Class IC: Diuretics for patients with fluid retention to improve symptoms

70 2013 ACCF/AHA Guideline for the Management of Heart Failure. Yancy CW, et al. Circulation. 2013;128:e240-e327.

Morbidity Benefit of Digoxin in HFpEF

71

Study (N)

Drug HF Severity Class

Target dose

Outcome

DIG Dataset (N=1832) Propensity -matched HFrEF and HFpEF

Patients

Digoxin II-III, EF >40% after diuretics and ACEI for 2 mos

0.125-0.5 mg/d

↓in 2y HF hospitalization: HFpEF: HR 0.64, (95% CI 0.45-0.90), P=0.010 HFrEF: HR 0.73, (95% CI 0.54-0.97), P=0.033 ↓in 2y HF hospitalization or mortality: HFpEF: HR 0.69, (95% CI 0.5-0.95), P=0.025 HFrEF: HR 0.72, (95% CI 0.55-0.99), P=0.0022

Meyer P, et al. Am J Cardiol .2008;102:1681-6.

Practical Points For Using Digoxin in HF o  Initiate at a dose of 0.125 mg daily or every other day

▪  Watch dosing and titration in elderly, renal dysfunction, low lean body mass

▪  Loading dose not necessary when using for HF

o  Goal plasma concentration 0.5-0.9 ng/mL o  Watch electrolytes or medications that may increase the risk of

digoxin toxicity ▪  Hypokalemia, hypomagnesemia, hypothyroidism

▪  Amiodarone, dronedarone, verapamil, propafenone, itraconazole, clarithromycin

72

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Effects of Device Therapy on HF Mortality/Morbidity Reduction

73

Study (N)

Therapy

HF Severity Class Avg F/U period

Outcome

MADIT-II (N=1232)1

Conventional (n=490) ICD (n=742)

Post-MI LVD, EF ≤ 30%

20 mo ↓31% in mortality, P=0.016

COMPANION

(N=1520)2 Pharmacotherapy (n=308) Pharmacotherapy + pacemaker (n=617) Pharmacotherapy + pacemaker/Defibrillator (n=595)

III/IV, EF ≤ 35%, QRS >120 msec

16 mo ↓36% in mortality, P=0.003

SCD-HeFT (N=2521)3

Conventional (n=847) Conventional + amiodarone (n=845) Conventional + single-lead ICD (n=829)

II/III, EF ≤ 35% 45.5 mo ↓23% in mortality, P=0.007

CARE-HF (N=813)4

Medical therapy (n=404) CRT (n=409)

III/IV, EF ≤ 35%, QRS >120 msec

29.4 mo ↓36% in mortality, P<0.002

MADIT-CRT

(N=1820)5 ICD (n=731) CRT + ICD (n=1089)

I/II, EF ≤ 30%, QRS >130 msec

2.4 y ↓34%, (in all-cause mortality or first HF event), P=0.001

RAFT

(N=1798)6 ICD (n=904) CRT + ICD (n=894)

II/III, EF ≤ 30%, QRS >120 msec

40 mo ↓25% in mortality, P<0.003

1. Moss A, et al. New Engl J Med.2002;346:877-83; 2. Bristow M, et al. N Engl J Med. 2004;350:2140-50; 3. Bardy G, et al. N Engl J Med. 2005;352:225-37; 4. Cleland JG, et al. N Engl J Med. 2005;352:1539-49; 5. Moss AJ, et al. N Engl J Med. 2009;362:1329-38; 6. Tang AS, et al. N Engl J Med. 2010;363:2385-95.

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