congestive heart failure 2015 - · pdf file9/21/15 1 congestive heart failure 2015 jp mehegan/...

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9/21/15 1 Congestive Heart Failure 2015 JP Mehegan/ Mercy Cardiology Definition Cardiac failure; Congestive heart failure; Chronic heart failure (synonyms) When the heart is unable to pump sufficiently and at the appropriate pressure to meet the bodies needs Symptoms; dyspnea, edema, fatigue; activity intolerance STARTING POINT Types of Heart Failure Systolic ; heart failure with abnormal LV function; ejection fraction < 40% Diastolic; heart failure with normal LV systolic function and abnormal cardiac relaxation (diastolic function); 50% Other; valvular, ischemia, MI, constriction/pericardial disease The Problem (USA) • 5,000,000 patients 6,500,000 hospital days / year • 300,000 deaths / year • More than half of those diagnosed will be dead in 5 years • 6% of health care budget (38 billion) • Incidence doubling in last ten years Heart Failure Costs 60% Inpatient care $23.1 billion 39% Outpatient care $14.7 billion 1% Transplants $270 million Total = $38.1 billion (5.4% of total healthcare costs) OConnell JB et al. J Heart Lung Transplant. 1994;13:S107-S112 Stages in the evolution of Heart Failure A. HF risk factors; no documented heart disease or symptoms B. Heart disease; no symptoms. Asymptomatic LV dysfunction C. Prior or current symptomatic CHF D. Refractory HF symptoms AHA / ACC HF guidelines 2005

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Page 1: Congestive Heart Failure 2015 - · PDF file9/21/15 1 Congestive Heart Failure 2015 JP Mehegan/ Mercy Cardiology Definition! Cardiac failure; Congestive heart failure; Chronic heart

9/21/15

1

Congestive Heart Failure 2015

JP Mehegan/ Mercy Cardiology

Definition

n  Cardiac failure; Congestive heart failure; Chronic heart failure (synonyms)

n  When the heart is unable to pump sufficiently and at the appropriate pressure to meet the bodies needs

n  Symptoms; dyspnea, edema, fatigue; activity intolerance

n  STARTING POINT

Types of Heart Failure

n  Systolic ; heart failure with abnormal LV function; ejection fraction < 40%

n  Diastolic; heart failure with normal LV systolic function and abnormal cardiac relaxation (diastolic function); 50%

n  Other; valvular, ischemia, MI, constriction/pericardial disease

The Problem (USA)• 5,000,000 patients• 6,500,000 hospital days / year• 300,000 deaths / year• More than half of those diagnosed will be

dead in 5 years• 6% of health care budget (38 billion)• Incidence doubling in last ten years

Heart Failure Costs

60% Inpatient care $23.1 billion

39% Outpatient care

$14.7 billion

1% Transplants $270 million Total = $38.1 billion

(5.4% of total healthcare costs)

O’Connell JB et al. J Heart Lung Transplant. 1994;13:S107-S112

Stages in the evolutionof Heart Failure

n  A. HF risk factors; no documented heart disease or symptoms

n  B. Heart disease; no symptoms. Asymptomatic LV dysfunction

n  C. Prior or current symptomatic CHFn  D. Refractory HF symptoms

AHA / ACC HF guidelines 2005

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Stages in Prevention and Treatment of Heart Failure

n  A. Treat risk factors, avoid toxins. ACE-In  B. ACE-I, Beta blockersn  C. ACE-I, Beta blockers, dig, diuretics,

aldosterone antagonists, ARB, resynchronization (Bi-V pacing), new therapies

n  D. Ultrafiltration, inotrope therapy, VADs and transplant

Classification of Functional Status; NYHA

n  1. No physical limitationsn  2. Symptoms with moderate activity,

exercise.n  3. Symptoms with mild activity; activities

of daily livingn  4. Symptoms at rest

Initial / Ongoing Evaluation

n  H&Pn  Assess functional capacity (NYHA, 6 min

walk)n  Assess volume status: (edema, rales, jugular,

hepatomegaly, body weight)n  Lab assessment: routine: electrolytes, renal

function, ECHO, X ray ,TSH, EKGn  BNP

Causes of Cardiomyopathy/ CHF

n  135 Causes of cardiomyopathyn  CAD; prior MI, diffuse ischemia (70%)n  Hypertensionn  Endocrine; diabetes, thyroidn  Drugs/ Toxins; ETOH, cocaine, chemon  Afib/ flutter; rate relatedn  Infection, familial, nutritional, idiopathic

B type natriuretic peptide!BNP

n  Role in the emergency room70 yo with PND, orthopnea, edema and vascular congestion on CXR70 yo with COPD, wheezing, rales and edema, clear CXR

n  Role in the clinic

Treatment Objectives

n  Increase Survivaln  Improve LV functionn  Improve symptoms/ Quality of Lifen  Improve exercise capacityn  Block neurohormonal changes and

prevent progressive HFn  CHF Trials App ($2.99)

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Beta blocker

Mineralocorticoid receptor

antagonist

Drugs That Reduce Mortality in Heart Failure With Reduced Ejection Fraction

ACE inhibitor

Angiotensin receptor blocker

Drugs that inhibit the renin-angiotensin system have modest effects on

survival

Based on results of SOLVD-Treatment, CHARM-Alternative, COPERNICUS, MERIT-HF, CIBIS II, RALES and EMPHASIS-HF

10%

20%

30%

40%

0%

% D

ecre

ase

in M

orta

lity

TreatmentPharmacologic Therapy

n ACE inhibitors/ARBs/Vasodilators

n Beta Blockersn Diureticsn  Digitalisn  Spironolactone/ Eplerenome

ACE-I. Clinical Effects

n  Improve symptomsn Reduce remodeling / progressionn Reduce hospitalizationn  Improve survival

ACE-i Practical Usen  Start with low dosen  Increase dose as toleratedn  Renal function & serum K+ after 1-2

weeksn  Dose NOT determined by symptoms n  Target randomized trial doses n  Reduce diuretics if possible

Mortality Reduction with ACE-i

Study ACE-i Clinical SettingCONSENSUS (1987) Enalapril CHFSOLVD treatment Enalapril CHFAIRE Ramipril CHFVheft-II Enalapril CHFTRACE Trandolapril CHF SAVE Captopril LVD/MISMILE Zofenopril High risk HOPE (2000) Ramipril High risk

ACE-i Dose (mg)

Initial MaximumCaptopril 6.25 / 8h 50 / 8hEnalapril 2.5 / 12 h 10 to 20 / 12hFosinopril 5 to 10 / day 40 / dayLisinopril 2.5 to 5.0 / day 20 to 40 / dayQuinapril 10 / 12 h 40 / 12 hRamipril 1.25 to 2.5 / day 10 / day

AHA / ACC HF guidelines 2005

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ACE-i Adverse Effects

n Hypotensionn Worsening renal functionn Hyperkalemian Cough 5-10%(iron pill may prevent)n Angioedema (1/1000)n Rash, ageusia, neutropenia (1-2%)n ACE intolerant use ARB

Angiotensin Receptor Blockers!ARBs

n  As added therapyn  As alternative therapy (ACEi intolerant)n  FDA approved; Valsartan 40 mg BID

start, 160 mg BID targetn  Candesartan; 4 mg QD start, 32 mg QD

targetn  Most commonly used ( not approved and

underdosed), Losartan, target 150 mg QD

Val-HeFT5010 patients ���

≥18 years; EF <40%; NYHA II-IV; LVIDd >2.9 cm/m2

ACE inhibitors, diuretics,���digoxin, β-blockers

Valsartan���40 mg bid titrated to���

160 mg bid

Randomized to

Receiving background therapy

Placebo

Cohn JN et al. Eur J Heart Fail. 2000;2:439-446.

Effect of Valsartan on Combined Morbidity/Mortality Endpoint*

Months3 6 9 12 15 18 21 24 270

6570758085909510

0

Probability of Event-

Free Survival���

0

*All-cause mortality, sudden death with resuscitation, hospitalization for worsening heart failure, or therapy with IV inotropes or vasodilators. Cohn JN et al. N Engl J Med. 2001;345:1667-1675.

30

ValsartanPlacebo

P = 0.00913.2% Risk Reduction

Reduction in Combined Morbidity/Mortality Endpoint* with Valsartan (No ACE-I Subgroup)

Hazard ratio (Cox model) : 0.560*First morbid event, including death or hospitalization

Time Since Randomization (months)

4050

6070

8090

100

0 3 6 9 12 15 18 21 24 27 30

P < 0.00144.0% Risk reduction

Valsartan, n=185

Placebo, n=181

Probability of Event-

Free probability���

Maggioni et al. J Am Coll Cardiol 2002;40:1414-21

CHARM

7,601 patients with heart failure 3 Individual component randomized trials with the ARB candesartan (4

or 8 mg/day, titrated to target dose of 32 mg) or placebo

CHARM Added §  Patients with LVEF

<40% and treated with an ACE-inhibitor

CHARM Alternative

§  Patients with LVEF <40% and

ACE-inhibitor intolerant

CHARM Preserved §  Patients with LVEF >40%

with or without ACE-inhibitor

Endpoints (follow-up minimum 2 years): ! Primary – Component trials: cardiovascular mortality or HF hospitalization

! Primary – Overall trial results: All-cause mortality

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SS-25

At risk, n Placebo 1272 1017 852 736 338 Candesartan 1276 1074 914 793 395

Primary Outcome !CV Death or CHF Hospitalization !

CHARM Added

1 2 3 Time, yr

0

10

20

30

40

50 Placebo

Candesartan %

3.5

HR 0.85 (95% CI: 0.75, 0.96), p = 0.011 Adjusted HR = 0.85, p = 0.010

483 (37.9%) 538 (42.3%)

15% risk reduction

0

NNT = 23

ß-Adrenergic Blockers Mechanism of action

n  Increase Density of ß1 receptorsn  Inhibit cardiotoxicity of catecholaminesn  Block Neurohormonal activationn  HRn  Antiischemicn  Antihypertensive•  Antiarrhythmic•  Antioxidant, Antiproliferative

ß-Adrenergic Blockers Clinical Effects

n  Improve symptoms (only long term)n  Reduce remodeling / progressionn  Improve LV systolic functionn  Reduce hospitalizationn  Reduce sudden deathn  Improve survival

ß-Adrenergic Blockers When to start

n  Patient stablen  Not volume overloadedn  No need for i.v. inotropic drugsn  Stable dose of ACEi /Diuretic/ Dig

ß-Adrenergic Blockers Contraindications

n  Asthma (not COPD)n  AV blockn  Symptomatic hypotension /

Bradycardia n  PVD and Diabetes are NOT

contraindications

ß-Adrenergic Blocker Adverse Effects

n  Hypotensionn  Fluid retention / worsening heart failuren  Fatiguen  Bradycardia / heart block

n  Reduce dosen  Consider cardiac pacingn  DON’T GIVE UP

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ß-Adrenergic Blockers Dose (mg)

Initial TargetBisoprolol 1.25 / 24h 10 / 24hCarvedilol 3.125 / 12h 25 / 12h

Carvedilol XL 10/ 24h 80/24hMetoprolol succinnate 12.5-25 / 24h 200 / 24h

Start Low, Increase SlowlyIncrease the dose every 2 - 4 weeks

35% ReductionIn death

Carvedilol Effect on Survival

What is Target Dose?

What is Target Dose

Which Agent Should We Use?n  Substantial differences in Beta–Blocking Agents

n  Beta-1 Selectivityn  Alpha-1 blockaden  Ancillary Properties

n Antioxidant n Endothelin regulation

COMET!Carvedilol vs Metoprolol Tartrate

n  5.7%mortalityn  reduction

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Digitalis. Clinical Effects

n  Improve symptoms and measured exercise

n  Reduction in hospitalization for CHFn  Does not improve survival

DIG trial

N=6800

NYHA II-III

N Engl J Med 1997;336:525

Digitalis. Indications

In combination with ACE-i + diuretics if persisting symptoms

AF, to slow AV conduction

Dose 0.125 to 0.250 mg / day

AHA / ACC Guidelines 2005

Diuretics. Indications

1.Symptomatic HF, with fluid retention•  Edema•  Dyspnea•  Lung Rales•  Jugular distension•  Hepatomegaly•  Pulmonary edema (Xray)

Loop Diuretics / Thiazides. Practical Use

n  Start with low dose. Titrate to achieve dry weight

n  Monitor serum K+ / renal function at “frequent intervals”

n  Reduce dose when fluid retention is controlled

n  Teach the patient when, how to change dosen  Combine to overcome “resistance”n  Do not use alone

Loop diuretics. Dose (mg)

Initial Maximum

Bumetanide 0.5 to 1.0 / 12-24h 10 / day

Furosemide 20 to 40 / 12-24h 400 / day

Torsemide 10 to 20 / 12-24h 200 / day

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Thiazides, Loop Diuretics. Adverse Effects

• K+, Mg+ wasting (sudden death???)• Na+

• Stimulation of neurohormonal activity• Hyperuricemia (15 - 40%)• Hypotension. Ototoxicity. Metabolic Alkalosis.

Diuretic Resistancen  Neurohormonal activationn  Hypertrophy of distal nephronn  Reduced tubular secretion (renal failure,

NSAIDs)n  Decreased renal perfusion (low output)n  Altered absortion of diureticn  Noncompliance with drugs/ Dennys

biscuits and gravy

Managing Resistance to Diuretics

• Restrict Na+/H2O intake (Monitor Sodium)• Increase dose (individual dose, frequency, i.v.)

• Combine: furosemide + thiazide / spiro / metolazone

• Reduce dose of ACE-I Stop NSAIDS• Dopamine (increase cardiac output)

Aldosterone in Heart Failure

n  Levels up 20X from normaln  Produces adverse effects

n  Cardiac remodelingn  Na++ retentionn  Up SNSn  Down arterial compliance

RALES Trial

n  1663 patientsn  LVEF greater than or equal to 35n  NYHA III-IVn  Spitonolactone or placebo in addition to

standard therapy

RALES Trial; Mortality Data

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Adverse Effects of Spironolactone

RALES Clinical

Hyperkalemia NA 34%

Mild NA 34%

Severe 2% 11%

Azotemia NA 12%

EMPHASIS-­‐HF:  Major  results

EMPHASIS-HF

Outcome Eplerenone (%)

Placebo (%) Adjusted hazard ratio (95% CI)

p

Cardiovascular death/heart-failure hospitalization

18.3 25.9 0.63 (0.54–0.74) <0.001

Cardiovascular death 10.8 13.5 0.76 (0.61–0.94) 0.01 Heart-failure hospitalization 12.0 18.4 0.58 (0.47–0.70) <0.001 Hospitalization for hyperkalemia

0.3 0.2 1.15 (0.25–5.31) 0.85

NYHA  Class  II  HF  (N=2737)  LV  EF  <  30%  Eplerenone  25-­‐50mg  QD  vs.  Placebo  

Aldosterone Antagonist Recomendations

n  Add to standard treatment if:n  Advanced symptomsn  No contraindications

n  Increased K +n Azotemia

n  Follow K+ and BUN/Cr

Aldosterone Antagonist Recomendations

n  Decrease KCL by 50%n  Lab Follow-up

n  Low riskn K+ and BUN/Cr level at week 1& 4

n  High Riskn K+ and BUN/Cr level at day 3 and at week 1 & 4

PARADIGM-HF

n  Entresto formerly LCZ696n  Approved July 2015n  ARB-Neprilysin inhibition vs enalapril 10

mg BIDn  Valsartan-Sacubitriln  Starting dose 49/51 mg BID, target 97/103

BID

Neprilysin Inhibition Potentiates Actions of Endogenous Vasoactive Peptides That Counter

Maladaptive Mechanisms in Heart Failure

Inactive metabolites

Neurohormonal activation

Vascular tone Cardiac fibrosis,

hypertrophy Sodium retention

Neprilysin Neprilysin inhibition

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0

16

32

40

24

8

Enalapril (n=4212)

360 720 1080 0 180 540 900 1260

Days After Randomization 4187 4212

3922 3883

3663 3579

3018 2922

2257 2123

1544 1488

896 853

249 236

LCZ696 Enalapril

Patients at Risk

1117

Kap

lan-

Mei

er

Estim

ate

of C

umul

ativ

e R

ates

(%

)

914

LCZ696 (n=4187)

HR = 0.80 (0.73-0.87) P = 0.0000002

Number needed to treat = 21

PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint)

LCZ696 (n=4187)

Enalapril (n=4212)

P Value

Prospectively identified adverse events Symptomatic hypotension 588 388 < 0.001 Serum potassium > 6.0 mmol/l 181 236 0.007 Serum creatinine ≥ 2.5 mg/dl 139 188 0.007 Cough 474 601 < 0.001

Discontinuation for adverse event 449 516 0.02 Discontinuation for hypotension 36 29 NS Discontinuation for hyperkalemia 11 15 NS Discontinuation for renal impairment 29 59 0.001

Angioedema (adjudicated) Medications, no hospitalization 16 9 NS Hospitalized; no airway compromise 3 1 NS Airway compromise 0 0 ----

PARADIGM-HF: Adverse Events

10%

Angiotensin Neprilysin Inhibition With LCZ696 Doubles Effect on Cardiovascular Death of Current

Inhibitors of the Renin-Angiotensin System

20%

30%

40%

ACE inhibitor

Angiotensin receptor blocker

0%

% D

ecre

ase

in M

orta

lity

18%

20%

Effect of ARB vs placebo derived from CHARM-Alternative trial Effect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial

Effect of LCZ696 vs ACE inhibitor derived from PARADIGM-HF trial

Angiotensin neprilysin inhibition

15%

ENTRESTO

n  Entresto $400/month, $4800/yearn  Enalapril $4/ month $48/ year

Biventricular pacing

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Cardiac resynchronization