Evaluation and Management of Heart Failure

S. Carolina Masri, MD

Division of Cardiology

University of Washington

Disclosures

No financial disclosures

No conflict of interest

Objectives

Frame the epidemiology of HF

Discuss evidence-based pharmacotherapies on reduced ejection fraction

Explore the utility of guideline directed medical therapies (GDMT)

At age 40, lifetime risk is 20 % in both genders

About 50% HFrEF, 50% preserved

Mortality rate 50% within 5 years

1-month readmission rate is ~25 %

Population Group Prevalence Incidence Mortality

Hospital Discharges Cost

Total population

5,700,000 670,000 277,193 990,000$39.2 billion

4

Heart Failure Epidemic in US

ACCF/AHA Guidelines 2013

Chronic Heart Failure Groups

Classification LV EF % Description

HFrEF ≤ 40 Effective therapies well-established

HFpEF ≥ 50 “Diastolic HF”, challenging diagnosis, therapies unclear

a. HFpEF, borderline

41 – 49 Intermediate group, clinically more similar to HFpEF

b. HFpEF, improved

> 40 Recovered HFrEF, not well characterized

Yancy C et al. ACCF/AHA 2013 Guidelines

100

75

50

25

0I II III IV

1

10

NYHA CLASS

Ann

ual S

urvi

val R

ate

Hos

pita

lizat

ions

/ y

ear

.1

Deceased

Adapted from Bristow, MR Management of Heart Failure, Heart Disease: A Textbook of Cardiovascular Medicine, 6th edition, ed. Braunwald et al.

Survival RateHospitalizations

Heart Failure Progression

Heart Failure Progression

New York Heart Association Functional Classification

Class I: No symptoms with ordinary activity

Class II: Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, dyspnea, or angina

Class III: Marked limitation of physical activity. Comfortable at rest, but less than ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain

Class IV: Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency may be present even at rest

Stages of CHF — ACC/AHA Guidelines 2005

AHigh-risk patients

Hypertension, diabetes, coronary disease, family history, cardiotoxic drugs

BStructural heart disease

LVH, MI, low LVEF, dilatation, valvular disease

C

Prior or current HF symptoms

D

Refractory

22%

34%

12%

0.2%

5 year survival Prevalence

20%

75%

96%

97%

Revised August 2005 from Jessup M, Brozena S. NEJM 2003;348:2003

Risk factor reduction, patient and family educationTreat HTN, DM, CAD, dyslipidemia. ACEI or ARB

ACEI, BB in all. Is patient candidate for surgery?Sodium restriction, diuretics

Aldosterone antagonistsDigoxin

InotropeVAD, TX

Stage AHigh riskwith no

symptoms

CRT, ICD if applicable

Stage BStructural

heart disease,

no symptoms

Stage CStructuraldisease,prior orcurrent

symptoms

Stage DRefractorysymptomsrequiring special

intervention

Stages & steps: treatment of systolic HF

Hospice

Brief inotrope

ACEI, ARB’s if intolerant of ACEI, BB if MI or low LVEF

(#1) 75 year old man with non-ischemic CM is admitted tooutside hospital. BNP on admission is 500 pg/mL. He istransferred immediately to your institution for furthermanagement. NT-proBNP at your hospital the following dayis 2300 pg/mL. Which of the following is true?

a) His clinical condition has worsened since his initial

presentation

b) The BNP and NT-proBNP values are approximately

Equivalent

c) Natriuretic peptide levels are not useful in the elderly

d) None of the above

Structure and Cleavage of NT-proBNP/BNP

T ½ = 2 hours T ½ = 22 minutes

Both digested by NEPs and cleared renally

NT-ProBNP vs BNP

NT-ProBNP values between 5-10 times BNP value in same patient

Both are affected by age (NT-ProBNP more)

Both affected by renal function

BNP and diagnosis of HF: Breathing Not Properly Trial

Dyspneic patients in the ED setting

ROC for BNP was 0.91, more accurate than H+P findings

Cutpoint of 100 pg/mL for all pt: Sensitivity 90%, specificity 76%

Maisel et al. N Engl J Med 347:161-167, 2002

Conditions that Influence BNP Concentrations

Increased BNP

Age (older)

Sex (female)

Renal dysfunction

MI/ACS

Right-sided heart failure (corpulmonale, PE)

High output failure (cirrhosis,septic shock)

Decreased BNP

ObesityEarly acute heart failure (less than 1 hr)

Heart Fail Rev 8:327-334, 2003.

Logeart et al, JACC 2004

Death or hospitalization after admission stratified by pre-discharge BNP

BNP/NT-proBNP

Heart Failure Pathophysiology

Myocardial injury (CAD, HTN, CM, Valvular disease)

Fall in LV performance ↑ wall stress

Activation of RAAS, SNS and Cytokines

Morbidity and Mortality

Peripheral vasoconstrictionHemodynamic alterations

Heart Failure symptoms

ANPBNPANPBNP

Remodeling and Progressive worsening

of LV function

Myocardial Toxicity

Goals in the Management of Heart Failure

Stabilize the patient –

– Make the patient feel better

Stabilize the disease process

– Keep the patient alive, out of the hospital, and feeling better

(#2) Ms LA is a 62 year old female with systolic heart failure LVEF 32 % in CF II of NYHA. She becomes an expert on HF management from reading wikipedia. She is wondering which of the following will improve her chance of survival?

a) β-blocker, ACE-I, aldosterone antagonists

b) β-blocker, ACE-I, aldosterone antagonists, diuretics

c) β-blocker, ACE-I, aldosterone antagonists, digoxin

d) All of the above

e) None of the above

Diuretics

Used to relieve fluid retention and treat symptoms

Diuretics do NOT decrease mortality

In fact, observational studies have shown association of higher doses with worse survival

Sodium Reabsorption Sites in the Nephron

Proximal Tubule

70%Distal Tubule

20%

5%

1-4%

Loop of Henle

Collecting

Tubule

Glomerulus

Thiazide Diuretics

Loop Diuretics

Mineralocorticoid

Receptor antagonist

Bioavailability of Loop Diuretics

100%

80%

50%

10%

-

-

-

furosemide torsemide bumetanide

Additional points about diuretics

1 mg Bumetanide= 20 mg torsemide = 40 mg furosemide

Furosemide PO to IV conversion is 2:1

Bumetanide and torsemide PO to IV conversion are 1:1

Consider ethacrynic acid if true allergy to loop diuretics

Sulfa moiety in antibiotics is not the same as loop diuretics

Diuretics: Guideline-Based Recommendations

Indication To improve symptoms in fluid overload

Considerations wheregreater diuresisneeded.(Diuretic refractoriness)

Increased dose – 2 or 3 times daily dosing provides more diuresisConsider switch to oral torsemide/bumetanide if persistent fluid retention despite high dose of furosemideConsider adding chlorothiazides or metolazone.Try to avoid chronic daily metolazone use: high potential for electrolyte imbalance and volume depletion.Intravenous administration

Monitoring BMP, symptomatic hypotension, renal dysfunction, especially with high dose and combination use.

When treatment goalachieved

Consider dose reduction or even discontinuation if improved clinical status

Monitor carefully for recurrent fluid retention.

Patient education Weight and fluid monitoring Selected patients may adjust dose to weight / clinical change

ACCF/AHA 2013: Common DiureticsDrug Initial Dose Max Dose Duration of Action

Loop Diuretics

Bumetanide 0.5-1.0 mg 1-2x/d 10 mg 4-6 h

Furosemide 20-40 mg 1-2x/d 600 mg 6-8 h

Torsemide 10-20 mg 1x/d 200 mg 12-16 h

Thiazide Diuretics

Hydrochlorothiazide 25 -100 mg 1-2x/d 200 mg 6-12 h

Metolazone 2.5-10 mg with loop diuretic 20 mg 12-24 h

Chlorothiazide (IV) 500 mg with loop diuretic N/A N/A

K-sparing Diuretics

Amiloride 5 mg 1x/d 20 mg 24 h

Spironolactone 12.5-25.0 mg 1x/d 50 mg 1-3 h

Triamterene 50-75 mg 2x/d 200 mg 7-9 h

Adapted from: Yancy C et al. ACCF/AHA 2013 Guidelines

(#3)-Your patient Mr G has recently been discharged from the hospital on lisinopril 10 mg bid, furosemide 40 mg qd and low doses of carvedilol 6.25 mg bid. On his visit to the clinic one week after dismissal, he reported feeling well, able to climb 2 flights of stairs, no PND or orthopnea. His weight has been stable, no swollen of LE.

VS: BP: 110/60 mmHg, HR: 78 bpm ,reg rhytm

PE: No JVD, no gallop, CTA bilaterally, no peripheral edema, warm and well perfused. Normal mentation

Labs: Creatinine: 1.7 mg/dl ( prior to discharged was 1.3 mg/dl)K: 4.9 mEq/LBNP: 250 pg/ml upon admission was 1040 pg/ml

(#3)-Cont’dThe most appropriate step at this point include which of the following?

a)Discontinue treatment with lisinopril and start with

hydralazine/isosorbide dinitrate.

b)Discontinue treatment with lisinopril and start with candesartan

c)Decrease the doses to half of lisinopril

d)Continues with the same treatment

RAAS Pathway: ACE-I

Angiotensinogen

Non-ACE pathways(eg, chymase)

Vasoconstriction Cell growth Na/H2O retention Sympathetic activation

Renin Angiotensin I

Angiotensin II

ACE

Cough,angioedema

Benefits? Bradykinin

Inactivefragments

Vasodilation Antiproliferation

(kinins)

Aldosterone AT2

AT1

ACEI in Chronic Heart FailureJAMA 1995;273:1450

Metanalysis - ACEi trials in Heart Failure N~7,500 patients

Death 23%

Death/HF Hosp 35%

Heart Failure Death 31%

Sudden Death 9%

Reinfarction 18%

Selected ACE-I Trials: Mortality

Low vs.High dose

ACE-I vs.ISDN/Hydra

Class I* Benefit forhospitalizationTrend for ACM;Low backgroundmortality; 12 yearf/u significant

CONSENSUS SOLVDTreatment

SOLVDPrevention

VHeFT II ATLAS

N 253 2569 4228 804 3164

LVEF Not reported < 35% < 35% < 45% < 30%

NYHA IV II-IV I I-IV II-IV

ACE-I Enalapril Enalapril Enalapril Enalapril Lisinopril 32.5-35 mg

Mortality in comparator

36% in placebo arm at 12 mo

40% in placebo arm at 41 mo

16% in placebo arm at 37 mo

25% in HYD/NIT armat 24 mo

42% in Lisinopril 2.5-5 mg at 46 mo

RRR 31% 16% No difference 28% No difference

Adapted from: Griffin BP et al. Cleveland Clinic Cardiology Board Review

When to Use ACE Inhibitors?

All HF patients with LVEF <40% should be treated with an ACE-I and a beta-blocker, unless a specific contraindication exists

(Class I, Level A)

Jessup et al, Circulation 2009

Optimal Dosing of ACE Inhibitors

• General Guideline:

• Start low and titrate to the target dose used in the clinical trials or the MAXIMUM TOLERATED DOSE(ATLAS trial)

• Captopril 6.25-12.5 mg 50 mg BID-TID (SAVE)

• Enalapril 2.5 mg BID 20 mg BID (SOLVD/X)

• Ramipril 2.5 mg BID 5 mg BID (AIRE/EX)

• Lisinopril 2.5-5 mg QD 30-40 mg OD (GISSI 3)

• Trandolapril 1mg 4 mg (TRACE)

ACE – Pearls

Up to 85-90% tolerate ACEIs

Start with low dose, especially in elderly

Follow-up BMP in 1-2 weeks

Titrate/double dose to target every 1-2 weeks

Bedtime dosing once BB introduced

Most ACEIs now on $ 4 generic lists

Remember some ACE inhibitor is better than no ACE inhibitor

ACEI or ARB - pearls

Worsening renal function

10% to 30% creatinine can be anticipated with ACE -and it is not an indication to discontinue treatment:

Avoid sodium and volume depletion Reduce diuretic dose Fluid resuscitation, salt liberalization Avoid NSAIDs

Hyperkalemia

Incidence ~ 3-10%, [K+] > 5.5 mEq/L

Drug Interactions: NSAIDs, KCL supplements,

Additional considerations: ACE-I

ACE-I can cause angioedema

Bilateral RAS is a contraindication to ACE-I

AVOID during pregnancy

Can increase bradykinin, resulting in cough

Generally used as 1st line therapy due to vasodilation even during ADHF

Inability to tolerate ACE-I is a bad prognostic sign

RAAS Pathway: ARB

Angiotensinogen

Non-ACE pathways(eg, chymase)

Vasoconstriction Cell growth Na/H2O retention Sympathetic activation

Renin Angiotensin I

Angiotensin II

ACE

Cough,angioedema

Benefits? Bradykinin

Inactivefragments

Vasodilation Antiproliferation

(kinins)

Aldosterone AT2

AT1

ARB in Heart Failure

Questions

Alternative to ACEI ?

Better than ACEI ?

Added to ACEI ?

Granger CB, et al. Lancet. 2003;362:772-776.

CHARM-Alternative: ARB vs. Placebo

Number at risk

Candesartan 1,013 929 831 434 122

Placebo 1,015 887 798 427 126

0 1 2 3Years

0

10

20

30

40

50

Placebo

Candesartan (intolerant of ACE-I)

HR 0.77 (95% CI 0.67-0.89), P=.0004Adjusted HR 0.70, P<.0001

3.5

406 (40.0%)

334 (33.0%)

Pro

po

rtio

n W

ith

CV

Dea

th

or

CH

F H

osp

ital

izat

ion

(%

)

Primary outcome of CV death or CHF hospitalization

ARB vs. ACE-I

No clear difference between ACE-I and ARB, with some trials favoring ARB, and others trending toward ACE-I superiority

ARB in addition to ACE-I

ARB added to ACE-I had no impact on all-causemortality in any of the major cardiovascular trials

ACEI/ARBs : Low vs Higher doses

Higher doses HF hospitalizations > Death

ATLAS - Lisinopril 5 vs 35 mg 24% vs. 8%HEAAL - Losartan 50 vs 150 mg 13% vs 6%

ARBs Doses in HF

ARBs

Candesartan 4-8 mg qd 32 mg qd 24 mg/day

Losartan 25-50 mg qd 150 mg qd 129 mg/day

Valsartan 20-40 mg bid 160 mg bid 254 mg/day

Starting HF doses! Target HF doses! Mean doses achieved in trials!

Mineralocorticoids receptors antagonist

Direct aldosterone antagonism in LV remodeling:

Decreased local fibrosis

Increased local dilation via increased NO

Decrease cardiac NE release, SCD

Benefits in 1-3 months

Spironolactone

Placebo

Months

RR = 0.70P < 0.001

Pro

bab

ility

of

Su

rviv

al

0.40

0.50

0.60

0.70

0.80

0.90

1.00

0 12 24 36

Epleronone

Placebo

RR = 0.85P < 0.008

0.40

0.50

0.60

0.70

0.80

0.90

1.00

0 12 24 36

Months

RR = 0.78P = 0.014

MRAs Beneficial in HFrEF and Post-MI LVD

30% Risk Reduction 15% Risk Reduction

0 12 24 36

0.50

0.70

0.80

0.90

0.40

1.00

0.60

Epleronone

Placebo

22% Risk Reduction

RALES(Severe HFrEF)

EPHESUS(Post-MI)

EMPHASIS(Mild HFrEF)

Reviews of Mechanisms : Pitt Heart Fail Rev 2012; Kamalov,…,Weber JCV Pharm 2013

Pitt NEJM 1999 Pitt NEJM 2003 Zannad NEJM 2011

Months

When to use aldosterone blockers?ACCF/AHA 2013:

-Recommended for NYHA class II-IV HF with LVEF ≤ 35%.

-After acute MI with LVEF ≤ 40% or history of diabetes

Contraindications

SCr > 2.5 men, SCr > 2.0 women (eGFR < 30 ml/min)

Acute renal insufficiency Hyperkalemia, K+ > 5

Aldosterone Blockers Pearls

Decrease mortality by 15-30%

Start low spiro/eplerenone 12.5-25 mg/day.

Target doses 25-50 mg/day.

• Follow-up BMP after initiation, dose change:

3 days then,1 week then,monthly for 3 months then,

Every 3 months indefinitely

Eplerenone is generic $28/month at UWMC Pharmacy

– Less Gynecomastia 1% vs. 10%

– Less impotence

(#4)You are asked to evaluate a 60 year old woman AAwho is admitted for treatment of cellulitis. She is doing well , but nurses has been refusing to administer her lisinopril and carvedilol due to low blood pressure. She has stable NYHA Class II symptoms. She is not lightheadedness. Her BP usually range of 75/50-80/55 mmHg. Her LVEF is 28 %.

Meds:Lisinopril 20 mg qd, Carvedilol 12.5 mg bid, furosemide 20 mg qd, Spironolactone 12.5 mg qd

VS: BP: 80/50 HR : 66 bpm regular

PE: No JVD, no gallop, CTA bilaterally, no peripheral edema, warm and well perfused. Normal mentation

(#4)-Cont’dWhich one of the following represent the most appropriate next step?

a)Hold the lisinopril and carvedilol completely

b)Reduce the doses of lisinopril and carvedilol by half and

follow up with the cardiologist as outpatient

c)Discontinue lisinopril and start hydralazine/isordil

d)Continues same doses of lisinopril and carvedilol

How Do Beta Blockers Improve Heart Failure?

Reverse LV remodeling, adrenergic receptors

Reduces risk of sudden cardiac death

Benefits in 3-6 months

Contraindications:

Severe bronchospastic disease

Severe, unpaced, symptomatic bradycardia HR < 50

Unpaced 2nd or 3rd degree AV Block

Effect of Beta Blockade on Outcome in Patients With HF and Post-MI LVD

BB in HFrEF

Drug Starting HF

Doses Target HF Doses

Mean Dose Achieved in

Trials

Bisoprolol 1.25 mg qd 10 mg qd 8.6 mg/day

Carvedilol 3.125 mg bid (with food)

25 mg bid (<85 kg) 50 mg bid (>85 kg)

37 mg/day

Carvedilol CR 10 mg qd 80 mg qd n/a

Metoprolol Succinate CR/XL

12.5-25 mg qd 200 mg qd 159 mg/day

BB -Recommendations

General Recommended for symptomatic and asymptomatic patients with reduced LVEF (≤ 40%) to reduce M&M.

Initiation; Dosing;

Initiate at low dosesUp-titrate gradually, generally ≥ 2 week intervals

Target doses shown to be effective in clinical trials

Target dose in 8-12 wks;Maintain at maximum tolerated dose

Beta Blockers -Pearls

If symptoms worsen or side effects appear

Adjust dose of diuretic Continue titration to target dose once symptoms at baseline.

If an acute exacerbation of chronic HF occurs

Maintain therapy if possible.Reduce dosage if necessary.Avoid abrupt discontinuation.If discontinued or reduced, reinstate gradually before discharge

Following decompensation

Initiate after optimizing volume status and discontinuation of intravenous inotropic agents.

Whenever possible, initiate prior to hospital discharge in stable patients.

Should we increase ACE-/ARB to target doses before beginning BB?

Titrating to target doses provides more benefit than very low doses.

However, the difference in efficacy between intermediate and high doses is small.

Thus, not unreasonable to start β-blockers after intermediate doses of ACEI are achieved, or vice versa.

Do not reduce or discontinue ACEI or β-blockers for asymptomatic low BP measurement

Hydralazine and Nitrates

Rationale is to reduce preload and afterload by both venous and arterial vasodilation

Hydralazine is predominately an arterial vasodilator

Nitrates are mostly venodilators

Increases NO bioavailability since nitrates are NO donors and hydralazine may have antioxidant effects

What about Hydralazine and Isordil? The A-HeFT Trial

1050 NYHA III/IV AA pts

LVEF < 35%

Composite endpt (death, HF hosp, QOL), Terminated early

– Hyd 75/Isordil 40 TID

– Mean - Hyd 142/Isordil 76

– ACE/ARB 86%

– BB 74%

– Spiro 39%

– Digoxin 59%

Ann Taylor et al.NEJM 2004;351:2049-57

Mortality 43%, p=0.02Do non-black patients benefit from hydralizine/nitrates?

Su

rviv

al %

Days Since Baseline Visit

43% Decrease in Mortality

Fixed Dose ISDN/HDZN

Placebo

P = 0.01

85

90

95

100

0 100 200 300 400 500 600

Hydralazine-Nitrate Combination -Guideline-Based Recommendations

Medical Therapy for Stage C HFrEF: Magnitude of Benefit Demonstrated in RCTs

GDMTRR

Reduction in Mortality

NNT for Mortality Reduction

(Standardized to 36 mo)

RR Reductionin HF

Hospitalizations

ACE - or ARB 17% 26 31%

Beta blocker 34% 9 41%

Aldosterone antagonist

30% 6 35%

Hydralazine/nitrate 43% 7 33%

Pharmacotherapy: Digoxin The oldest cardiac drug still in contemporary use

• Inhibits Na-K ATPase increases contractility

• Neurohormonal effects decreased SNS activation, vagomimetic Slows AV conduction

Digoxin: DIG Trial (NEJM 1997)

Reduces hospitalization

But does NOT reduce mortality

Narrow therapeutic window : Digoxin level should be < 1.0 (0.5 to 0.9) ng/mL

Monitor closely for digoxin toxicity

Renewed interest in certain subgroups? Subanalyses suggest that sicker patients may have additional benefit (EF < 25%, NYHA III-IV)

Vincent van Gogh’s yellow period and digitalis

Starry nightDr. Gachet at a Table with Sprig of Foxglove

Digoxin Toxicity

Symptoms: Fatigue, anorexia, diarrhea, yellow halos, confusion, agitation

Classic arrhythmias seen with toxicity:

- Paroxysmal atrial tachycardia w/ block

- Accelerated junctional rhythm

- Bidirectional ventricular tachycardia (only dig and CPVT can do this)

Electrolyte abnormalities that predispose to dig tox:

- Low Mg, Low K, High Ca

PARADIGM HF – Valsartan-LCZ696 NEJM 2014

PARADIGM HF – Valsartan-LCZ696NEJM 2014

Composite 20%

CV death 20%

HF Hosp 21%

Mortality 16%

First medication to replace a HF medication (ACEI)

Enalapril 10 mg BID vs. Valsartan-Neprilysin 200 mg BID in 8442 patients NYHA 2-4, EF ≤ 35%, BNP >150 or >100 if HF Hospitalization <12 months. On ACEI/ARB with SBP ≥100 and eGFR>30.

F/U 27 months

Evidence-Based Treatment for Heart Failure with Reduced LVEF

Control VolumeReduce Mortality

Sodium Restriction*Diuretics*

Digoxin*

-BlockerACEIor ARB

AldosteroneAntagonist

Treat Residual SymptomsCRT

an ICD*Hyd/ISDN*

*For select indicated patients.

ICD*

Treat Comorbidities

Aspirin*Warfarin*

Statin*

Enhance Adherence

EducationDisease Management

Performance Improvement Systems18

Potential Impact of Optimal Implementation of Evidence-Based HF Therapies on Mortality

Fonarow GC, et al. Am Heart J 2011;161:1024-1030.

Guideline Recommended

Therapy

HF Patient

Population Eligible

for Treatment, n*

Current HF

Population

Eligible and

Untreated, n (%)

Potential Lives

Saved per Year

ACEI/ARB 2,459,644 501,767 (20.4) 6516

Beta-blocker 2,512,560 361,809 (14.4) 12,922

Aldosterone Antagonist 603,014 385,326 (63.9) 21,407

Hydralazine/Nitrate 150,754 139,749 (92.7) 6655

CRT 326,151 199,604 (61.2) 8317

ICD 1,725,732 852,512 (49.4) 12,179

Total - - 67,996

Improved Adherence to ACC/AHA HF Guidelines Translates to Improved Clinical Outcomes in Real World HF Patients

Each 10% improvement in ACC/AHA guideline-recommended composite care was associated with a 13% lower odds of 24-month mortality (P<0.0001)

Fonarow GC, et al. Circulation. 2011;123:1601-1610.

Case# 56 y/o male caucasian admitted in 10/2014 because of AHF. Normal coronary arteries and cardiac MRI without evidence of acute myocarditis and or infiltrative disease

Echocardiogram 10/14 Echocardiogram 3/15

Meds: Metoprolol XL 200 mg qd, Lisinopril 20 mg qd, Spironolactone 12.5 mg qd, Now off diuretics

Conclusions

HF remains common and costly in the current era, with increasing incidence and prevalence

Heart failure medications can reduce mortality by 60-70%

Effort should be made to implement guideline-recommended therapies in HF patients in absence of contraindications or intolerance

High risk patients Inability to tolerate or need to withdraw HF medications

Low BP, Sodium

High Diuretic dose, BUN, Creatinine, BNP

Recurrent hospitalizations

Thank you for your attention!

ARB vs. ACE-I

No clear difference between ACE-I and ARB, with some trials favoring ARB, and others trending toward ACE-I superiority

ELITE I ELITE II OPTIMAAL VALIANT

N 722 3152 5477 9818

Admission criteria

EF < 40%NYHA II-IVAge > 65 y

EF < 40%NYHA II-IVAge > 60 y

MI w/ anterior Q waves or clinical HF or EF < 35% or LVEDD > 65 mm

EF < 40% or clinical HF

Ischemic etiology

68% 79% 100% post-MI 100% post-MI

ARB Losartan Losartan Losartan Valsartan

Comparator Captopril Captopril Captopril Captopril

Mortality 46% RRR at 12 mo

No difference at18.2 mo

No difference at32.4 mo

No difference at24.7 mo

Adapted from: Griffin BP et al. Cleveland Clinic Cardiology Board Review

ARB in addition to ACE-I

ARB added to ACE-I had no impact on all-cause mortality in any of the major cardiovascular trials

ValHEFT CHARM Added VALIANT

N 5010 2548 9794

LVEF < 40% < 40% < 40% or clinical HF

NYHA II-IV II-IV I-IV

Ischemic etiology

57% 62% 100%

ARB Valsartan Candesartan Valsartan

ACE-I use 93% on ACE-I 100% on ACE-I 100% on captopril

Mortality No difference at 23 mo

No difference at41 mo

No difference at24.7 mo

Adapted from: Griffin BP et al. Cleveland Clinic Cardiology Board Review

Carvedilol vs Metoprolol Succinate

Usefulness of Torsemide after Admission for ADHF

234 pts admitted for ADHF

torsemide furosemide

52% HF Hospitalization

(Murray, et al. Am J Med 2000;111:513-521)

Randomized on Discharge

DIG Trial (NEJM 1997)

HF with EF < 45% on ACE and diuretic

N = 6800 Mean EF 28%

Mortality

Death or HF Hosp

MERIT-HF Study Group. Effect of Metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). LANCET. 1999;353:2001-07.

Severity of Heart FailureMode of Death

12%

24%

64%

CHF

Other

SuddenDeath

n = 103

NYHA II

26%

15%

59%

CHF

Other

SuddenDeath

n = 103

NYHA III

56%

11%

33%

CHF

Other

SuddenDeath

n = 27

NYHA IV

Neprilysin Inhibition Potentiates Actions of Endogenous Vasoactive Peptides That Counter

Maladaptive Mechanisms in Heart Failure

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