HF Primary Care Roadmap · 3 HFpEF vs HFrEF 1) HF w/ Reduced EF (HFrEF), Systolic: EF ≤ 40% 2) HF...

1

Jennifer Jones, MD

North Florida Regional Medical Ctr.

Family Medicine GME Program

[email protected]

HF Primary Care Roadmap

HFrEF

Diuretics

Digoxin

ACE/ARB

β-Blocker Aldosterone Antagonist

Ivabradine

Sacubitril-Valsartan

Lifestyle Modification: H20/Na+ Restriction; Flu & Pneumovax;

Weight Management; Exercise/Cardiac Rehab

Disease

Modifying Rx

Symptom

Modifying Rx

ECHO / BNP HFpEF

Comorbidities: HTN, Anemia, COPD, ETOH, CAD, Arrhythmia

Cardiology

Consult AICD/CRT

ISDN/Hydralazine (African Am)

HF: The Hemodynamic Malignancy

“The prognosis of affected individuals is dismal,

as fewer than 50% of these people survive 5

years from the time of initial Dx.” - Mulrow C. JAMA 1987;259(23):3422-3425

“Mortality from CHF is high, averaging 30%

within the 1st year, 50% by 3-4 years, and 80%

by 6-10 years” – Anderson J. Modern Medicine 1987;55(May)

2


Prospective Cohort Study (n= 558)

Total Mortality at 5 years

Systolic Dysfunction= 42%

Diastolic Dysfunction = 25%

MacCarthy PA, Kearney MT, Nolan J, et al. “Prognosis in heart failure with preserved left

ventricular systolic function: prospective cohort study” BMJ 2003; 327:78-9.

“Although survival has improved, the

absolute mortality rates for HF remain

~50% within 5 yrs of dx.”

-2013 ACCF/AHA Guidelines


Clyde W. Yancy et al. Circulation. 2013;128:1810-1852

Definition of HF

Clinical syndrome resulting from structural or functional

impairment of ventricular filling or ejection of blood.

• Exercise Intolerance (dyspnea & fatigue)

• Fluid Retention (NOT everyone; ≠CHF)

Cardiac output(CO) ≠ tissue metabolic requirement

Sustained Sympathetic Nervous Sys (SNS) Activation

Sustained RAAS activation


3

HFpEF vs HFrEF

1) HF w/ Reduced EF (HFrEF), Systolic: EF ≤ 40%

2) HF w/ Preserved EF (HFpEF), Diastolic : EF > 50%

& clinical syndrome HF, abnormal LV diastolic filling

• ~50%; more challenging dx

• Elderly female w/ HTN; Obese, CAD, DM, Afib, HLD

HFpEF, borderline: EF = 41-49%

HFpEF previously with HFrEF


Functional Classifications

ACCF/AHA: development & progression of dz

NYHA: exercise capacity & symptomatic status

Stages are progressive

• Progression ↓ 5-yr survival; ↑ BNP


ACCF/AHA Stages of HF NYHA

A At high risk but Asymptomatic +

NO structural heart disease

B Structural heart dz but

Asymptomatic I

C Structural heart dz with current

or prior symptoms I-IV

D Refractory HF IV

Clyde W. Yancy et al. Circulation. 2013;128:1810-1852c

4

Functional Classifications: NYHA

Criteria Committee of the New York Heart Association, 1964.

Class I Ordinary physical activity does NOT cause

undue fatigue, palpitations, SOB +/or angina.

Class II Ordinary physical activity causes undue Sx

Class III < ordinary physical activity causes undue Sx

Class IV Sx with any physical activity or at rest

Functional Classifications: NYHA

Strenuous→Sx (Class I)

Ordinary → Sx (Class II)

Minimal → Sx (Class III)

Anything → Sx (Class IV)

Neurohormones

• ↑ SNS/Catecholamines

• ↑ RAAS (A-II, ADH)

• ↑ANP/BNP

• LV Remodeling

• ↓CO

• Systolic dysfxn

• Diastolic dysfxn

• Combined dysfxn

G. Hasenfuss and D. Mann. Braunwald’s Heart Disease: A Textbook of CV Medicine, 22, 454-472.e3

Ischemia

HTN

Myopathy

Compensation Consequence

5

…once upon a time, a young man

was walking his elephant….

The Story of RAAS

Lots & lots

Of

Blood

OUCH!

RAAS To The RESCUE!!

• A-I: Selective Vasoconstriction

• NE: Vascular Tone, Heart Rate, Contractility

• Aldosterone: Salt, Water retention, Thirst

Argggh!

Ssshhh…

I’m Hiding.

6

• Selective vasoconstriction bleeding stopped • Flow maintained to muscles, heart, brain • 4 quarts low: heart beat faster, harder • Insensitive fluid losses (saliva, sweat, urine) • Thirsty

…and they all LIVED

happily ever after

• ↑ SNS/Catecholamines

• ↑ RAAS (A-II, ADH)

• ↑ANP/BNP

• LV Remodeling

• ↓CO

• Systolic dysfxn

• Diastolic dysfxn

• Combined dysfxn

G. Hasenfuss and D. Mann. Braunwald’s Heart Disease: A Textbook of CV Medicine, 22, 454-472.e3

Index Event

Ischemia

HTN

Myopathy

Compensation Consequence

7

RAAS ⇆ HF

Aldosterone

Angiotensinogen

Na+ retention/ ↑ IVV

Angiotensin I

Angiotensin II

Vasoconstrict/↑SVR

RENIN

ACE

Angiotensin II NE Aldosterone

Blastic Cardiac Fibroblast

Collagen

Proliferation

Clastic Cardiac Fibroblast

Collagen

Degradation

RAA Hyperactivation Excess collagen

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Brain Natriuretic Peptide (BNP)

• First isolated in porcine brain

• Synthesized but not stored in ventricular myocytes

• Ventricular Stress (↑ LVEDP) ↑ BNP

Cheung BM, Kumana CR. “Natriuretic Peptides-Relevance in Cardiovascular Disease.” JAMA.

1998;280(23):1983-1984.

BNP : Potential Clinical Roles

1) Diagnosis or Exclusion of HF

2) Monitor CHF progress/Guide Rx

3) Prognostic Indicator/Preventing Readmission

–Congestion End-diastolic wall stress ↑BNP

–Studies show congestion may precede Ac.HF Sx by 7-10 days

Maisel AS, Daniels LB. Breathing Not Properly 10 Years Later: What We Have Learned and What We

Still Need to Learn. J Am Coll Cardiol.2012;60(4):277-282.

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Causes for ↑ Natriuretic Peptide Levels

Cardiac Noncardiac

Heart failure, including RV

Acute coronary syndrome

Heart muscle dz (LVH)

Valvular heart disease

Pericardial disease

Atrial fibrillation

Myocarditis

Cardiac surgery

Cardioversion

Advancing age

Anemia

Renal failure

Pulm: OSA; PNA, Pulm HTN

Critical illness

Bacterial sepsis

Severe burns

Toxic-metabolic insults (eg

chemotherapy, envenomation)


*Decreased levels in Obesity

BNP: Diagnostic Role

• Study: n=250 Pts w/ Ac. SOB in VA Urgent

Care/ED

• 2 Cardiologists retrospectively reviewed clinical

data (blinded to BNP) and made an opinion as to

etiology

Dao Q, Krishnaswamy P, Kazanegra R, et al. “Utility of B-Type Natriuretic Peptide in the

Dx of CHF in an Urgent Care Setting.” J Am Coll Cardiol. 2001 Feb;37(2):379-85.

BNP Levels in Dyspneic Pts

0

200

400

600

800

1000

1200

COPD (n=56) CHF (n=94)

COPD (n=56)

CHF (n=94)

86 ± 39

1076 ± 138

BN

P C

on

ce

ntr

ati

on

(p

g/m

l)



10

BNP: CHF Severity

0

500

1000

1500

2000

2500

Mild (n=27) Moderate (n=34) Severe (n=36)

186 ± 22

791 ± 165

2013 ± 266

BN

P C

on

cen

tra

tio

n (

pg

/ml)



• BNP ≥80 pg/ml accurately predicted dx of CHF (95%)

• BNP <80 pg/ml had high negative predictive value (98%).

• BNP measurements could have potentially corrected 29

of the 30 diagnoses missed by urgent-care physicians.

BNP: Diagnostic Role



STARS-BNP: BNP-guided Tx

• n=220 NYHA II-III pts on ACE, BB, diuretics randomized:

– Clinical Group (tx guided by HF specialists/guidelines)

– BNP Group (tx guided to target BNP <100 pg/ml)

• F/u every month x 3 mos q3 mos x ~15 mos

• 1° Outcome: HF related Death or Hospitalization

Jourdain P, et al. Plasma BNP-guided therapy to improve outcome in heart failure: the STARS-BNP

Multicenter Study. J Am Coll Cardiol. 2007 Apr 24;49(16):1733-9.

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STARS-BNP: Results

BNP grp: fewer

HF Deaths and

Hospitalizations

(24% vs 52%)



EV

EN

T F

RE

E S

UR

VIV

AL

(%

)

DAYS (15 mos)

BNP

Clinical

p<0.001

STARS-BNP: Results

At 3 months,

more med Δ’s

in the BNP grp

w/ higher mean

dosages of

ACEIs and BBs



Breathing Not Properly (BNP) Study: Dx and Prognosis

• Prospective Obs. study; n=1,586 w/ Ac. SOB

• 2 Dx Methods compared to Cardiologist Dx

1. NHANES and Framingham criteria for Dx CHF

2. BNP

• OUTCOME:

– Single BNP more accurate than criteria scores for Dx of CHF

– pts whose 30d BNP level was > discharge BNP level were at

highest risk for decompensation/readmission

Maisel AS, Daniels LB. Breathing Not Properly 10 Years Later: What We Have Learned and What We

Still Need to Learn. J Am Coll Cardiol.2012;60(4):277-282.

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BNP Study: Obesity and BNP Levels

52 35 25

643

462

247

BMI < 25 25≤ BMI <35 BMI ≥ 35

No Acute CHF Acute CHF

BN

P (

pg

/mL

)

Daniels LB, Clopton P, et al. How Obesity Affects the Cut-Points for B-Type Natriuretic Peptide in the

Diagnosis of Acute Heart Failure. Am Heart J. 2006;151(5):999-1005.

P<0.05)

170

110

54

0

20

40

60

80

100

120

140

160

180

BMI < 25 25≤ BMI < 35 BMI ≥ 35 Daniels LB, Clopton P, et al. How Obesity Affects the Cut-Points for B-Type Natriuretic Peptide in the

Diagnosis of Acute Heart Failure. Am Heart J. 2006;151(5):999-1005.

BNP Study: Obesity and BNP Levels 90% Sensitivity BNP cut-offs for different BMIs

BN

P (

pg

/ml)

BNP: Good for Dx, Guided Tx & Px

• “Although trials examining BNP-guided HF management

were small, 2 comprehensive meta-analysis showed

BNP-guided Tx reduces all-cause mortality in pts w/

chronic HF vs usual clinical care….this may be

attributed to increased achievement of GDMT.”

• Falsely low levels in obesity and HFpEF.

Clyde W. Yancy et al. 2013 ACCF/AHA HF Guideline. Circulation. 2013;128:1810-1852.

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Noninvasive Cardiac Imaging

Patients with suspected or new-onset HF, or

acute decompensated HF, should undergo a

chest x-ray to assess heart size and pulmonary

congestion, and detect alternative cardiac,

pulmonary, and other diseases that may cause

or contribute to the patients’ symptoms.

I IIa IIb III

Noninvasive Cardiac Imaging

A 2-D Echo w/ Doppler should be performed

for initial eval of pts presenting with HF to

assess ventricular fxn, size, wall thickness, wall

motion, and valve fxn.

Repeat Echo in pts w/ HF who have had

significant change in clinical status, received

GDMT, or candidate for device therapy.

I IIa IIb III

I IIa IIb III


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Goal Directed Medical Tx (GDMT) and HRQOL

HF decreases Health-Related Quality of Life (HRQOL)

Lack of improvement in HRQOL after hosp discharge is

a predictor of re-hospitalization and mortality

• ACE/ARBs modestly improve or delay progressive

worsening of HRQOL

• Cardiac Resynchronization therapy (CRT) and dz

management/education are shown to improve HRQOL


Stages in the development of HF and recommended therapy by stage.

Clyde W. Yancy et al. Circulation. 2013;128:e240-e327

STAGE A = At High risk for HF but w/o structural heart dz/Sx

e.g. Patients with:

• HTN

• ATH

• DM

• Obesity

• Or patients

• using

cardiotoxins

• w/ FH CM

Goals:

• Heart healthy lifestyle

• Prevent vasc/CAD

• Prevent LV structural

abnormalities

Drugs:

• ACEI/ARB (vasc dz or DM)

• Statins

Structural

Heart

Disease


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STAGE B: Structural Heart Dz w/o S/Sx HF

GOALS: DRUGS:

•Prevent HF Sx - ACE/ARB

•Prevent further Cardiac Remodeling -Beta Blockers

In Selected Patients: ICD or Revascularization or Valve Sx

Patients with:

• Prior MI

• LV Remodeling (LVH, Low EF)

• Valvular Disease

HF Sx

Develop


Modifiable Risk Factors

• HTN

• Salt Intake

• Dyslipidemia/ATH

• Obesity/Overweight

• Diabetes Mellitus

• Substance Abuse (ETOH/Tobb/Cocaine)

• AFib (rate control)

• OSA (CPAP improve EF/functional status)


BP Control

• Long-term tx of both systolic and diastolic HTN

reduces risk of HF by ~ 50%

– 2013 ACCF/AHA HF Guidelines

• SPRINT Trial (n=9,361)

–Non DM pts with HTN were ~40% less likely to

develop HF if treated to a goal SBP <120

compared to a SBP goal <140

The SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103-2016

16

BP Control: To Prevent HF Intensive BP Control Intensive BP Control in

pts w/ prior MI

Decreases

risk of new

HF by ~50%;

56% in DM2

Decreases

risk of HF by

~ 80%

Lancet 1991;338:1281:1281-5 (STOP-Hypertension).

UKPDS Group. UKPDS 38.BMJ 1998;317:703-713. JAMA 1997;278:121-6 (SHEP).

Sodium Restriction?

• Obs. study: 902 pts NYHA II-III; Systolic or Diastolic HF

• METHOD: Na+ intake assessed over 36 months using a

food freq. questionnaire; pts classified as either Na+

Restricted (<2500mg/d) or Unrestricted (≥2500 mg/d).

• OUTCOME: composite of death or HF hospitalization

Doukky R, Avery E, Mangla A, et al. Impact of Dietary Sodium Restriction on Heart Failure

Outcomes. JCHF. 2016;4(1):24-35.

Sodium Restriction?

• Na+ Restriction Higher Risk of HF hospitalization or

death (42% v 26%; HR 1.85; p=0.004)

• Highest risk increase in those not taking ACE/ARB

(HR 5.78; P=0.002) and NYHA II (HR 2.36; P=0.003)

• ACCF/AHA SOR for Na+ restriction downgraded

– Class I (recommended) Class IIa (reasonable)

Doukky R, Avery E, Mangla A, et al. Impact of Dietary Sodium Restriction on Heart Failure

Outcomes. JCHF. 2016;4(1):24-35.

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ACCF/AHA Guideline Rec on Na+

• “No study to date has evaluated the effects of Na+

restriction on neurohormonal activation and outcomes in

optimally treated HF pts.”

– 1 observational study that evaluated pts with HFpEF.

• Should Na+ recommendations vary w/ HF type, severity,

related comorbidities, or race?


Cardiac Rehabilitation

• “Cardiac rehab reduces mortality; improves

functional capacity, exercise duration, and

HRQOL and reduces hospitalizations.”

–ExTraMATCH Trial: Exercise Training Meta-

Analysis of Trials in pts with Chronic HF

–RCT (HF-ACTION Trial) did NOT show benefit w/

ex training except in subgrp of pts w/ CAD RFs


ExTraMATCH: Ex Training in HF 9 studies; n= 801; Training programs 8 wks to >1yr

ExTraMATCH Collaborative. BMJ 2004;328:189.

26%

43%

22%

32%

0%

10%

20%

30%

40%

50%

Mortality(HR 0.65; p=0.02)

Mortality or Admission(HR 0.72; p=0.01)

Control Exercise Training

18

Statistically Sig No Significant Diff ? Insuff Evidence

Transitional Care Interventions vs Usual Care for HF

AHRQ ↓ All-Cause

Readmit

↓HF

Readmit

↓Mortality ↓ # Hosp

Days

Home Visit Program

Phone Support

Multidisciplinary HF

Clinics ? ?

Nurse-Led HF Clinics ? ?

Guirguis-Blake J. Transitional Care Interventions to Prevent Readmissions for Patients with Heart Failure.

Am Fam Physician. 2016; 93(5):401-403.

AHRQ: HF Transitional Care Intervention

High-Intensity Home Visiting Programs (5+ visits)

–Meta-analysis (15 RCTs)

• 25% ↓ All-cause Readmits (n=1,563; NNT=9)

• 49% ↓ HF Readmits (n=282; NNT=7)

• 23% ↓ Mortality (n=1,693; NNT=33)

Structured Telephone Support

– Meta-analysis (13 RCTs)

• 26% ↓ HF Readmissions (n=1,790); NNT=14)

• 26% ↓ Mortality (n=2,011; NNT=27) Guirguis-Blake J. Transitional Care Interventions to Prevent Readmissions for Patients with Heart Failure.

Am Fam Physician. 2016; 93(5):401-403.

AHRQ: HF Transitional Care Interventions

Multidisciplinary HF Clinics: frequent regular

scheduled visits with multiple clinicians

–Meta-analysis (7 RCTs)

•30% ↓ All-Cause Readmits (n=336; NNT=8)

•44% ↓ Mortality (n=536; NNT=18)

Guirguis-Blake J. Transitional Care Interventions to Prevent Readmissions for Patients with Heart Failure.

Am Fam Physician. 2016; 93(5):401-403.

19

HFrEF Stage C (NYHA I-III) Treatment:

ACEI/ARB

and

BBlker

Hydral-

Nitrates

Loop

Diuretic

Volume Overloaded

(NYHA II-IV)

AA w/ persistant Sx

(NYHA III-IV)

CrCl>30mL/min

K+ <5.0mEq/dL

(NYHA II-IV)

ADD ADD ADD


Aldosterone

Antagonist

Class I Recommendations

NYHA I ???

Guideline Recommended HFrEF Txs Guideline Rec’d Tx RRR in RCTs NNT for Mortality (12 m)

ACE/ARB 17% 77

Beta-Blocker 34% 28

Aldosterone Antagonist 30% 18

Hydralazine + Nitrate * 43% 21

Cardiac Resynchronization (CRT) 36% 24

Implantable Cardioverter Defib (ICD) 23% 70

Colucci, WS. Overview of therapy in heart failure with reduced ejection fraction. In: UpToDate,

Post TW (Ed), UpToDate, Waltham, MA. (Accessed on March 31, 2016). Figure Modified. *African-Americans

• Evidence diuretics improve symptoms and

exercise tolerance in HF

• Loop diuretics (Bumetanide, furosemide, torsemide)

• Thiazides (Chlorthalidone, HCTZ, Metolazone)

• K-sparing (Spironolactone, Triamterene, Amiloride)

• Goal: eliminate clinical fluid retention

–Titrate to ↑UOP and ↓weight by 0.5-1.0 kg/d


20

ACE-Inhibitors in HFrEF

• Shown to reduce HF progression, mortality &

hospitalization; improve HRQOL

• Initiate at low doses and titrate to target dose

(shown to reduce CV risk in clinical trials)

– Lisinopril 20 mg/d

• Reassess renal function 1-2 weeks after initiation

Delahaye F, Gevigney G. Is the Optimal Dose of ACEI in Patients with CHF Definitely

Established? JACC. 2000;36(7): 2096-2097.

RAAS ⇆ HF

Aldosterone

Angiotensinogen

Na+ retention/ ↑ IVV

Angiotensin I

Angiotensin II

Vasoconstrict/↑SVR

RENIN

ACE

21

ACE Inhibitor RAA Modulation

Angiotensinogen

Bradykinin

Angiotensin I

Angiotensin II

RENIN

ACE

Inactive

Bradykinin

components

Aldosterone AT I

ACEI ACE

↑ ↑ NO

Bronchoconstriction

ARB

Fosinopril in Chr. HFrEF

• STUDY: RCT; N=241 NYHA II-III and LVEF 25±7%

• 24wk Fosinopril 10-20mg/d or Placebo

• OUTCOMES:

– ∆ max treadmill exercise time

– worsening heart failure (death, hosp, ED, NYHA progression)

Brown E, et al. Effects of fosinopril on exercise tolerance and clinical deterioration in patients with

chronic congestive heart failure not taking digitalis. Am Journal Card. 1995;75(8):596-600.

ETT improved w/ Fosinopril Group

+ 28.4

-13.5 -20

-15

-10

-5

0

5

10

15

20

25

30

35

Placebo Fosinopril

Tre

adm

ill E

xerc

ise

Tim

e (s

ecs)

p = 0.047



22

Fosinopril: NYHA Class Progression

13%

32%

24%

18%

Improved Worsened

Placebo

Fosinopril



p=0.003

-35%

-30%

-25%

-20%

-15%

-10%

-5%

0%

Sx Improvement/Worsening: Fosinopril

0%

10%

20%

30%

40%

50%

60%

70%

80%

Placebo

Fosinopril

30% 28%

70%

8%

15% 17%

33%

23%

29%

Brown E, et al. Am Journal Card. 1995;75(8):596-600.

% W

ors

ened

%

Imp

rove

d

Dyspnea Fatigue

PND

*p ≤ 0.002

16% 25%

14%

SOLVD: Enalapril in HFrEF

• STUDY: DB RCT; n=2,569 pts w/ Chr. HF (EF≤35%)

• Mean F/u 41 mos; Enalapril 2.5mg-20mg/day or Placebo

• OUTCOMES:

–1⁰ Death

–2⁰ Hospitalization + Death

The SOLVD Investigators. Effect of Enalapril on Survival in Patients with Reduced Left Ventricular

Ejection Fractions and Congestive Heart Failure. N Engl J Med 1991; 325:293-302.

23

SOLVD: Enalapril in HFrEF

40%

57%

35%

48%

0%

10%

20%

30%

40%

50%

60%

Death Hosp or Death

Placebo EnalaprilThe SOLVD Investigators. Effect of Enalapril on Survival in Patients with Reduced Left Ventricular

Ejection Fractions and Congestive Heart Failure. N Engl J Med 1991; 325:293-302.

p<0.05

SAVE: Captopril for HFrEF Post-MI

• N=2,231; 3-16d post-MI w/ EF ≤40% but w/o overt HF

• Mean f/u 42 months; Captopril or Placebo

• Outcomes: 1° Mortality

– CV Morbidity (severe CHF or recurrence of MI)

– CV Morbidity + Mortality

Pfeffer MA. Effect of Captopril on Mortality and Morbidity in Patients with Left Ventricular Dysfunction after Myocardial

Infarction — Results of the Survival and Ventricular Enlargement Trial. N Engl J Med. 1992;327(10):669-77.

Pfeffer MA et al. N Engl J Med 1992;327:669-677. Figure 3 Modified.

SAVE: CV Morbidity and Mortality.

Pla

ceb

o

Cap

top

ril

*p < 0.05

† p < 0.005

24

Any ACEI will do.

• Meta-Analysis 32 RCTs (n=7105); Rx min 8 wks

• Total Mortality (P<0.001)

Placebo 21.9% vs ACEI 15.8%

• Combined Mortality and Hospitalization for HF (P<0.001)

Placebo 32.6% vs ACEI 22.4%

• Benefits observed with several different ACE Inhibitors:

(Enalapril, Captopril, Ramipril, Quinapril, Lisinopril)

Garg R, Yusuf S. Overview of randomized trials of ACEIs on mortality and morbidity in patients with

heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA. 1995 May 10;273(18):1450-6

2013 ACCF/AHF HF Guidelines: ARBs

“ARBs are recommended in pts w/

HFrEF w/ current or prior Sx who are

ACEI intolerant, to reduce morbidity and

mortality.” (Class I Rec; LOE: A)


ARBS in Patients Not Taking ACE Inhibitors:

Val-HeFT & CHARM-Alternative

Val-HeFT

Valsartan

Placebo

p = 0.017

Months

Su

rviv

al

%

CV

De

ath

or

HF

Ho

sp

%

Placebo

Candesartan

CHARM-Alternative

HR 0.77, p = 0.0004

Months

Maggioni AP et al. JACC 2002;40:1422-4.

Granger CB et al. Lancet 2003;362:772-6.

50

60

70

80

90

100

0 3 6 9 12 15 18 21 24 27

0

10

20

30

40

50

0 9 18 27 36 42

25

2013 ACCF/AHA HF Guidelines: Beta-Blkers (BB)

“1 of the 3 BBs proven to reduce mortality

(bisoprolol, carvedilol, metoprolol succinate)

is recommended for ALL pts w/ current or prior

symptoms of HFrEF to reduce morbidity and

mortality.”

(Level of Evidence: A)


Beta-Blockers in HFrEF

• Lessen Sx of HF

• Improve clinical status

• Enhance overall sense of well-being

• Reduce mortality

• Reduce hospitalization

*Benefits observed in pts already on ACE inhibitors Clyde W. Yancy et al. 2013 ACCF/AHA HF Guideline. Circulation. 2013;128:1810-1852.

26

COPERNICUS: Carvedilol in HFrEF

• RCT; n=2,289 NYHA III-IV and EF <25%

• Placebo (n=1,133) vs. carvedilol (n=1156) x ave 10 mos

• OUTCOMES

–↓ Risk of CV Death or Hosp by 27% (p*)

–↓ Risk HF Death or Hosp by 31% (p*)

–↓ Days in Hosp by 27%; 40% fewer days for HF (p*)

–↓ Serious AE (worsened HF, cardiac death/shock, VT)

Milton Packer et al. Circulation. 2002;106:2194-2199 *p < 0.05

COPERNICUS: Time to CV Death or Hosp

Milton Packer et al. Circulation. 2002;106:2194-2199

↓ Risk of CV

Death or Hosp by

27%

(p=0.00002)

COPERNICUS: Time to HF Death or Hosp

Milton Packer et al. Circulation. 2002;106:2194-2199

↓ Risk of HF

Death or Hosp by

31%

(p=0.000004)

27

MERIT-HF: Metoprolol Succinate

• RCT; n=3,991 stable NYHA II-IV, EF ≤40%

(already on ACE, Digoxin, Hydralazine/Nitrate, Diuretic)

• Initially Randomized to:

– Metoprolol CR/XL 12.5mg or 25mg qd or Placebo

• Target: Metoprolol CR/XL 200mg qd (titrated x 8 wks)

– mean dose = 159mg/d

• 1° OUTCOME: All-Cause Mortality

MERIT-HF Study Group. The Lancet , Volume 353 , Issue 9169 , 2001 – 2007.

MERIT-HF: All-Cause Mortality

Reduction in

Total Mortality

7.2% vs 11 %

34% RRR (p=0.006)


Metoprolol CR/XL

Placebo

Cum

ulat

ive

Mor

talit

y, %

Follow-up, months

MERIT-HF: ↓ CV Hospitalizations

10% 10%

15% 10%

0%

5%

10%

15%

20%

25%

30%

Placebo Metoprolol CR/XL

CV Causes, Not HF Heart Failure

Metoprolol XL Placebo


28

Beta Blockers: Risk of Tx

• Adverse Rxns requiring attn:

– Fluid retention

–Worsened HF

– Fatigue

–Bradycardia/Heart block

–Hypotension


• Caution w/:

–Diabetics w/ recurrent hypoglycemia

–Asthma

–Resting limb ischemia

“Because of its favorable effects on survival and disease progression, a clinical trial-proven

BB should be initiated as soon as HFrEF is diagnosed…it should not be delayed until

disease progression.”

(Do not wait for adv dz; Add when stable)

2013 Guidelines: Don’t Delay


Which is the Better Beta-Blocker?

• No good head to head trials comparing BBs

– Metoprolol succinate, bisoprolol, carvedilol

– COMET Trial: doses not comparable; metoprolol tartrate

• Consider BP lowering effect (Carvedilol>Metoprolol)

–SR/XL Metoprolol Succinate

–Bisoprolol

–Carvedilol α-1, β-1, and β-2 receptors

Colucci WS. Rationale for and clinical trials of beta blockers in heart failure due to systolic dysfunction.

In: UpToDate, Gottlieb SS, UpToDate, Waltham, MA. (Accessed on April 1, 2016.)

β-1 Selective

29

RALES: Spironolactone in Severe HF

• 1,663 pts NYHA III-IV; LVEF ≤35% on ACEI/Loop (Dig and Vasodilators OK)

• Randomized to Spironolactone 25mg or Placebo

– Titrated to 50mg over 8 wks

• Mean f/u 24 mos

• OUTCOMES:

–1°: All-Cause Mortality

–2°: CV Mortality; CV Hospitalization; Δ NYHA class

Pitt B, Zannad F, Remme W. et al “The Effect of Spironolactone on Morbidity and Mortality in Pts with Severe Heart

Failure” N Engl J Med. 1999;341(10):709-17


0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

% Deaths

Placebo

Spironolactone35%

n=386

46%

n=284



p < 0.001

30




Risk of Death 30% lower with

Spironolactone vs Placebo (p*)

RALES Trial Spironolactone

(N=822)

Placebo

(N=841) p Value

CV Hospitalizations 32% 40% *

Improved NYHA Class 41% 33% *

No Δ NYHA Class 21% 18% *

Worsened NYHA Class 38% 48% *

Hyperkalemia 2% 1% NS

Gynecomastia 10% 1% *



RALES: Conclusion

“Blockade of aldosterone receptors by

spironolactone, in addition to standard tx,

↓ the risk of both morbidity and death

among patients with severe HF.”

N Engl J Med. 1999;341(10):709-17

31

EPHESUS: Eplerenone Post-Acute MI HF Efficacy and Survival Study

• 6,632 pts Post-MI HF pts

• Randomized to Eplerenone 25-50mg qd or Placebo x 16m

• OUTCOMES:

– All-Cause Mortality

– CV Death or Hospitalization

– Acute MI/CVA/Ventricular Arrhythmia

Pitt B, Remme W, Zannad F, et al. Eplerenone, a Selective Aldosterone Blocker, in Patients with Left

Ventricular Dysfunction after Myocardial Infarction. NEJM. 2003;348:1309-1321

EPHESUS: Eplerenone in Post MI HF

Pitt B et al NEJM 2003;348:1309-1321

Placebo

(16.7%)

Eplerenone

(14.4%)

All-

Cau

se M

ort

alit

y (%

)

Months since Randomization

Pitt B et al NEJM 2003;348:1309-1321

EPHESUS: Eplerenone in Post MI HF

Months since Randomization

CV

Dea

th o

r H

osp

ital

izat

ion

(%

)

Placebo

(30%)

Eplerenone

(27%)

32

EMPHASIS: Eplerenone in Mild Pts Hospitalization And Survival Study

• STUDY: 2,737 pts NYHA II; EF >30% on BB/ACEI

• Exclusion: NYHA III-IV, CKD, Acute MI

• Randomized to Eplerenone 25-50mg or Placebo x 21 mos

• OUTCOMES:

– Composite CV Death or 1st HF Hospitalization

– All-Cause Mortality

– HF Hospitalization

– Hyperkalemia

Zannad F et al. N Engl J Med 2011;364:11-21

EMPHASIS: Eplerenone in Mild HF


Eplerenone

(18.3%)

Placebo

(25.9%)

EMPHASIS: Eplerenone in Mild HF


Placebo

(15.5%)

Eplerenone

(12.5%)

33

Aldosterone Antagonist in HFrEF

“Clinicians should strongly consider the

addition of the aldosterone receptor

antagonists spironolactone or eplerenone

for all patients with HFrEF already on

ACEI (or ARBs) and BBs.” -2013 ACC/AHA Guidelines


A-HeFT: African Am Heart Failure Trial

• V-HeFT I: ISDN/H did NOT significantly reduce HF

mortality but positive trend (no ACEI)

• V-HEFT II: ISDN/H vs. ACEI showed ACEI more

beneficial, but ISDN/H more efficacious in AA cohort

• A-HeFT: ISDN/H in AA on ACE/ARB+BB+Aldosterone

Antagonist


34

A-HeFT: ISDN/Hydralazine in AA HF

• 1050 AA pts w/ NYHA III-IV on standard HF Tx

• Randomized to ISDN/H 20/37.5mg TID 40/75mg TID

or placebo

• Study ended early (18mos)

• 1° OUTCOME: Composite score of weight values for…

– All-Cause Death

– 1st HF Hosp

– HRQOL. Taylor AL, Ziesche S, Yancy C, et al “Combination of Isosorbide Dinitrate and Hydralazine in Blacks

with Heart Failure” N Engl J Med 2004;351:2049-57.

Taylor, A. et al. N Engl J Med 2004;351:2049-2057

A-HeFT Trial: Scoring System (Higher is Better)

Minnesota Living w/

HF Questionnaire

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

A-HeFT: 1° Outcome (*Higher is Better)


Mea

n 1

° C

om

po

site

Sco

re

ISDN/H

-0.1±1.9

Placebo

-0.5±2.0 p = 0.01

35

A-HeFT: Overall Survival *Mortality 10.2% (placebo) vs 6.2% (ISDN/H); p = 0.02


43% ↓ rate in

All-Cause Mortality

Ove

rall

Sur

viva

l (%

)

Days since Baseline Visit

Placebo

ISDN/H

A-HeFT: ∆ QOL Score (Lower is Better)

-6

-5

-4

-3

-2

-1

0

Placebo ISDN/H

∆ Q

OL

Sco

re

-5.6

-2.7


P = 0.02

A-HeFT: 1st HF Hospitalization

24.4%

16.4%

Placebo ISDN/H


p=0.001

36

A-HeFT: Adverse Events


2013 ACCF/AHA Recommendation

“The combination of ISDN/H is recommended

for pts self-described as AA w/ NYHA III-IV

HFrEF receiving optimal tx w/ ACEI/B-blkers.”

(Level of Evidence: A)


ACCF/ACC 2013 HF Guidelines:


37

Digoxin: DIG Trial

• RCT 6800 HF pts w/ LVEF ≤45%

–988 pts EF >45% in ancillary trial ║main study

• Randomized to Digoxin or Placebo

• F/U @ 4 wks, 16wks, then q4mos

• 1° Outcome: All-Cause Mortality

• 2° Outcome: HF Hosp, CV Death, Dig Tox

The Digitalis Investigation Group. The Effect of Digoxin on Mortality and Morbidity in Patients with Heart

Failure. N Engl J Med . Feb 20,1997; 336:525-533

DIG Trial: All-Cause Mortality



Digoxin (34.8%) vs. Placebo (35.1%); p=0.8

No Effect on Mortality

38

DIG Trial: Mortality Due to Worsening HF



*HF Hosp: Digoxin (13.4%) vs Placebo (17.4%); RR 0.72; p<0.001

No Difference

BUT…

Digoxin in HF

• DIG Trial Conclusion: “Digoxin tx is likely to affect the freq of hosp, but not survival.”

(no significant benefit seen in HFpEF)

• 2013 ACC/ACCF Guidelines

–Digoxin can be beneficial in pts w/ HFrEF to decrease hospitalizations for HF (LOE: B)



39

Ivabradine (Corlanor)

• Selective Inhibitor of the “funny channel (If)” which

modulates SA pacemaker ↓ Sinus Rate

• Does not effect atrial conduction, AV node, or ventricles

no effect on contractility

– Difference from BB and CCB

• Reduces HR by ~ 10 bpm ↓ cardiac workload

Colucci, WS. Use of beta blockers and ivabradine in heart failure with reduced ejection fraction. In:

UpToDate, Gottlieb SS (Ed), UpToDate, Waltham, MA. (Accessed on March 31, 2016).

SHIFT Trial: Systolic Heart Failure tx

with lf Inhibitor Ivabradine Trial

• RCT; 6558 pts w/ HF Sx and LVEF ≤ 35%

–HR ≥ 70bpm

–HF Admission in previous year

–On background GDMT (ACE/ARB, BB, Aldo Antagonist)

• 1° Outcome: CV Death or Hosp for worsening HF

Swedberg, Karl et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-

controlled study. The Lancet , Volume 376 , Issue 9744 , 875 – 885.

SHIFT: CV Death or Hosp for Worsening HF

0%

5%

10%

15%

20%

25%

Placebo Ivabradine

HF Hospitalization(p<0.0001)HF Death(p=0.014)CV Death

21%

3% 5%



16%

29% 24%

p<0.0001

40

• Serious AES

–Increased Sx’tic Bradycardia (5% vs 1%)

–Increased Visual side effects (3% vs 1%)

• Conclusion: HR reduction w/ Ivabradine ↓HF

Mortality and Hospitalizations for pts with

persistent HF Sx, HF > 70bpm on background tx

SHIFT Trial: Ivabradine in Chronic HF



Sacubitril-valsartan

• Sacubitril = neprilysin inhibitor

• Neprilysin inhibition ↑ vasoactive peptides

vasodilatation, natriuresis/diuresis, ↓ LV remodeling

• Indicated for NYHA II-IV HFrEF in place of ACE/ARB

• Increased risk of angioedema w/ concurrent ACEI

Colucci, WS and Pfeffer MA. Use of angiotensin II receptor blocker and neprilysin inhibitor in HF with

reduced EF. UptoDate, Gottlieb SS (Ed), UpToDate, Waltham, MA. (Accessed on April 12, 2016).

41

PARADIGM-HF: Sacubitril-valsartan in HFrEF

• 8442 HF NYHA II-IV and EF ≤ 40%

• Randomized to:

–LCZ696 (Sacubitril + Valsartan) 200mg BID

–Enalapril 10mg BID

• 27 months

• OUTCOMES:

–1° Outcome: Composite CV death or HF Hosp

–2° Outcomes: CV Death; All-Cause Death

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

PARADIGM-HF: 1° Outcome (CV Death or HF Hospitalization; HR 0.80, p*)

0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

30.0%

35.0%

Enalapril LCZ696

CV Death(HR 0.80; p*)

HF Hospitalization(HR 0.79; p*)

26.5% 21.8%

*p<0.001


PARADIGM-HF: All-Cause Mortality


42

PARADIGM-HF: Adverse Events

More Hypotension

Less Hyperkalemia

Less Renal Impairment


PARADIGM-HF: Conclusion

Sacubitril-losartan was superior to

enalapril in reducing risk of death and

risk of HF hospitalization.

*No guideline recommendations


43

HF Guideline Recommendations: ICD (Implantable Cardioverter-Defibrillator)

• 1° SCD prevention in pts > 40 days Post-MI, on GDMT and expected survival > 1 yr:

–nonischemic DCM or ischemic heart disease w/ EF ≤ 35%, NYHA II-III Sx (LOE: A)

–w/ EF ≤ 30%, NYHA I Sx (LOE: B)

• Refer to cardiology when EF ≤ 35% Clyde W. Yancy et al. 2013 ACCF/AHA HF Guideline. Circulation. 2013;128:1810-1852.

MADIT-II: Multictr Automatic Defib Implantation Trial II

Prophylactic ICD compared w/ standard of

care led to 31% RRR in all-cause mortality

in post-MI pts w/ EF ≤ 30%

-Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with

myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346:877–83.

HF Guidelines: Cardiac Resynchronization Therapy (CRT)

• CRT is indicated for pts w/ EF ≤ 35%, NSR,

LBBB, QRS ≥150ms, and NYHA class II-IV

Sx on GDMT

–May consider in non-LBBB pattern, QRS

duration 120-149ms, Afib

• Refer to cardiology when EF ≤ 35% Clyde W. Yancy et al. 2013 ACCF/AHA HF Guideline. Circulation. 2013;128:1810-1852.

44

MADIT-CRT Trial

CRT-ICD decreased risk of HF event in

ASx’tic pts (NYHA I-II) w/ LVEF ≤30% and

wide QRS (≥130ms)

–1 Outcome: All-cause death or Nonfatal HF

event (ICD-CRT 17.2% vs ICD alone

25.3%; HR 0.66; p=0.001)

Moss AJ, Hall WJ, et al. Cardiac-Resynchronization Therapy for the prevention of Heart Failure

Events. N Engl J Med 2009; 361:1329-1338.

HFpEF: ACCF/ACC 2013 Guidelines

• Control BP according to guidelines to ↓ morbidity (LOE C)

• Diuretics should be used for relief of Sx due to

volume overload in patients with HFpEF. (LOE: C)

*Piller LB, Baraniuk S, Simpson LM, et al. Long-term follow-up of participants with heart failure in the Antihypertensive and Lipid-Lowering

Treatment to Prevent Heart Attack Trial (ALLHAT). Circulation. 2011;124:1811–8.

Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358:1887–98.

45

• The use of ARBs might be considered to

decrease hospitalizations (LOE B)

–CHARM-Preserved Trial

• Candesartan did NOT ↓CV death compared to

Placebo in HFpEF

• HF Hosp was lower with Candesartan

(15% vs 18% in placebo grp; HR 0.84; p=0.047)

Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular

ejection fraction: the CHARM-Preserved Trial. The Lancet , Volume 362 , Issue 9386 , 777 - 781

HFpEF: ACCF/ACC 2013 Guidelines

HFpEF Management • No evidence has demonstrated mortality benefit of

neurohormonal antagonists (BB, ACE/ARBs) or CRT

• Tx contributing factors and comorbidities:

–HTN, Pulm Dz, CAD, AF, Obesity, Anemia, DM, CKD, OSA

• Exercise training has shown to improve exercise

capacity and quality of life in HFpEF.

Borlaug BA, Colucci, WS. Treatment and prognosis of heart failure with preserved ejection

fraction. In: UpToDate, Gottlieb SS(Ed), UpToDate, Waltham, MA. (Accessed on April 2, 2016).

HF Primary Care Roadmap

HFrEF

Diuretics

Digoxin

ACE/ARB

β-Blocker Aldosterone Antagonist

Ivabradine

Sacubitril-Valsartan

Lifestyle Modification: H20/Na+ Restriction; Flu & Pneumovax;

Weight Management; Exercise/Cardiac Rehab

Disease

Modifying Rx

Symptom

Modifying Rx

ECHO / BNP HFpEF

Comorbidities: HTN, Anemia, COPD, ETOH, CAD, Arrhythmia

Cardiology

Consult AICD/CRT

ISDN/Hydralazine (African Am)

HF Primary Care Roadmap · 3 HFpEF vs HFrEF 1) HF w/ Reduced EF (HFrEF), Systolic: EF ≤ 40% 2) HF...

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