Update on the Management of CHF

7/29/2019 Update on the Management of CHF

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DR. Dr. Anwar Santoso, SpJP(K), FIHA, FAsCCDept. of Cardiology

Vascular Medicine

School of MedicineUniversity of Indonesia

Update Management of

Congestive Heart Failure


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Estimated prevalence of 4.7 million patientsin the United States

400,000 new patients diagnosed and 250,000deaths annually

Five-year overall survival rate < 50% Economic burden approximately 5.4% of total

health care expenditure

Epidemiology


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Acute Decompensated Heart Failure

Most frequent reason for hospitalization in patients> 65 years of age in U.S.

Average duration of hospitalization 6 days

Rehospitalization within 6 months high as 50%

Hospitalizations increased from 600,000 (1985) to900,000 (1998) in U.S. mean LOS 7 days

mean charge per patient $10,000

Greatest expenditure for HF, annual inpatientmanagement, approximately $23 billion

Average 6-12 month mortality 35%

Incidence, Cost, Prognosis


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HF Population by NYHA Class

American Heart Associati

Class INo limitations of physical

activity

Class IISlight limitations of physical

activityClass IIIMarked limitations of physica

activity

Class IVInability to carry out physical

activities without discomfort

Class I1.68 M(35%)

Class IV240 K(5%)

Class III1.20 M(25%)

Class II1.68 M(35%)


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Hospitalization: Predominant

Contributor to Heart Failure Costs

60.6%Hospitalization

$23.1 billion

38.6%Outpatient care

$14.7 billion(3.4 visits/year

/patient)

0.7%

Transplants$270 millionTotal = $38.1 billion(5.4% of total healthcare costs)

OConnell JB et al. J Heart Lung Transplant1994; 13:S107-S1


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Hospital Visits for Heart Failure

Initial Episode 21%

Repeat Visit 79%

Rates of readmission 2% within 2 days

20% within 1 month 50% within 6 months


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Hospital Readmission for Heart Failure

17%

Other19%Failure to Seek

Care

16%

Inappropriate Rx

Rx Noncompliance24%

Diet Noncompliance24%

HFSA Research 20


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Cardiomyopathy

Dilated Cardiomyopathy Most common type

Characterized by systolic dysfunction

Moderate to severe reduction in LVEF

Hypertrophic Cardiomyopathy Characterized by filling abnormalities or diastolic

dysfunction

Systolic function is preserved initially Normal or increased LVEF


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Etiology

Ischemia

Ischemic Disease

HypertensionIschemia

Infarction

Diastolic Dysfunctio

HypertrophicCardiomyopathy

Primary dysfunction

Systolic Dysfunction

Nonischemic Disease

Valvular abnormalities

Structural damage

DilatedCardiomyopathy

Hypertension


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Pathophysiology

Cardiac Compensatory Adaptations

Remodeling of myocardial cells

Down-regulation of beta receptors

Extracardiac Compensatory Adaptations

Renin-angiotensin system (RAS)

Sympathetic nervous system (SNS)


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Pathophysiology

Renin-angiotensin system Sensitive to low CO

Stimulates vasoconstriction (increases afterload)

Conserves sodium/water (increases preload) Sympathetic nervous system

Sensitive to changes in BP

Promotes vasoconstriction (increases afterload)

May be directly cytotoxic to myocardial cells


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Diagnosis

Subjective and Objective Evaluation Signs and symptoms of left ventricular failure

Signs and symptoms of right ventricular failure

Echocardiography To determine etiology

To estimate severity of dysfunction

Radionuclide ventriculogram To assess severity of dysfunction


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Functional Class

Class I No limitation of physical activity.

Class II Slight limitation of physical activity.

Class III Marked limitation of physicalactivity.

Class IV Unable to carry on any physicalactivity without discomfort.


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Advanced Heart Failure

Noncompliance

diet

medications

Arrhythmias

Emotional stress

Administration ofinappropriatemedications

Myocardial infarction

Environmental factors

Inadequate therapy

Endocrine disorders

thyrotoxicosis

Pulmonary infection

Precipitating Facto


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Acute Decompensated Heart Failure

Fluid OverloadIncreased weight

Pulmonary edema

DOE, PND, orthopnea

rales, tachypnea,hypoxia

Peripheral edema

JVD/HJR

hepatic congestionlower extremity edema

Early satiety

Signs and Symptoms

Low Cardiac OutputFatigue

Nausea/vomiting

Early satiety

Decreased weightElevated serum

creatinine

BNP C i


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BNP ConcentrationsVariation with Absence/Presence HF

Mea

n

BNP

Concentration(pg/ml)

LV Dysfunction(n=14)

38 4141 31

1076 138

No CHF(n=139) CHF(n=97)

0

200

400

600

800

1000

1200

1400 P < 0.001


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BNP ConcentrationsVariation with Degree of HF Severity

BNPConcentra

tion(pg/ml)

186 22

791 165

2013 266

Mild(n=27)

Moderate(n=34)

Severe(n=36)

0

500

1000

1500

2000

2500


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Goals of Therapy

Prolong survival

Slow disease progression

Reduce hospitalization

Reduce symptoms

Improve quality of life

Chronic Heart Failure


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Goals of Therapy

Relieve pulmonary congestion

Decrease systemic vascular resistance

Improve myocardial systolic function

Improve myocardial diastolic function Preserve systemic perfusion pressure

Optimize oral drug therapy

Acute Heart Failure


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Case

55 YOF with newly diagnosed HF (LVEF 38%)

CC: SOB at rest/DOE PMH:

long-standing uncontrolled HTN, mild asthma, OA

EKG: NSR, 95 bpm

CXR: left lower lobe infiltrate Labs:

Na 134 mmol/l, K 4.8 mmol/l, BUN 24 mg/dl, sCr 1.5 mg/(baseline 1.2 mg/dl), WBC 21 K, pro-BNP 4,028 pg/ml


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Case (continued)

Physical exam:

BP 142/93, HR 95, RR 25, SaO2 93% on 4L NC

no JVD/HJR, S4, 1+ LEE to shins

rales throughout, mild crackles at bases Medications prior to admission:

HCTZ 25 mg qd, ramipril 5 mg qd, albuterol PRN, OTCnaproxen PRN


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Diuretics

Case Discussion

How can this hospitalization be avoided in the futur

How can the diuretic regimen be optimized?


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Non-Pharmacologic Therapy

Diet Low sodium

Low fat/cholesterol

Maintain Fluid Balance Restrict Na+ 2-3 g/d (1g Na = 2.5g NaCl)

Daily weight measurements to assess fluid changes Limit intake to 3 liters per day

Exercise Discourage intense isometric exercise

Encourage mild to moderate dynamic exercise Eliminate modifiable risk factors

Hypertension, smoking, diabetes, etc.


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Diuretics

Di i


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1999 Guideline No Recommendations

2005 Guideline

To be announced

Diuretics

HFSA Guideline Highlights


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-AdrenergicReceptor Blockers

B t Bl k


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Beta Blockers

Case Discussion

Does it matter which beta blocker or which dose?

What to do with beta blocker therapy in the hospita On beta blocker PTA? Should it be continued?

Not on beta blocker PTA? Should it be initiated? When?

Should there be any reason not to initiate betablocker therapy in this patient? Absolute contraindications?

Relative contraindications?

Should one beta blocker be preferred over another certain patient populations?

Beta Blockers


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34%Mortality: 34% 35%

Lancet. 1999;353:2001-2007.

MERIT-HF

Follow-up (months)

Cumulativemortality(%) 20

15

10

5

0

0 3 6 9 12 15 18 21

P=.0062 (adjusted)P=.00009 (nominal)

Placebo

Metoprolol CR/XL

n=3991

Time (Days)

CIBIS-II1.0.9.8.7.6

.5

.4

.3

.2

.1

0

Log rank P=.00006

Bisoprolol

Placebo

n=2647

0 200 400 600 800

Probab

ilityofsurvival

Lancet. 1999;353:9-13.

COPERNICUS

Carvedilol

Placebo

P=.00014 (unadjusted)

100

90

80

70

60

50

0 4 8 12 16 20 24

P=.0014 (adjusted)

n=2

%

Survival

Months

N Engl J Med. 2001;344:1651-1658

Beta BlockersSurvival Studies

Beta blockers


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Beta-blockersHFSA Guideline Highlights

1999 Guideline 7 Recommendations

Routinely administered to NYHA Class II-III (LVEF 40%)

Considered for NYHA Class I (LVEF 40%)

Insufficient evidence to recommend in NYHA Class IV

2005 Guideline

To be announced


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-Adrenergic Receptor BlockersInitial Dosing and Uptitration

Carvedi lo l

(Coreg)Metop rolo l CR/XL

(Toprol XL)Init ial Dose 3.125 mg bid NYHAc II 25 mg qd

NYHAc III 12.5 m Up-t i trat ion 6.25 m 12.5 m bid 50 mg, 100 mg qd

Tar et Dose 85 kg 50 mg bid

150 mg qd

B t Bl k


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Target Mean DosageDosage Achieved % TargetStudy (mg) (mg/day) (mg/day)

CIBIS-II 10 mg qd 7.5 75%Lancet1999

MERIT-HF 200 mg qd 159 80%Lancet1999

US Carvedilol 6.25-50 mg bid 45 94%NEJM1996 bid

COPERNICUS 25 bid 37 74%NEJM2001

Beta BlockersTarget Doses


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.

100

90

80

60

70

50

240 20161284 28

Placebo(n=1133)

Carvedilol(n=1156)

Months

% Survival

P=0.00014

COPERNICUSAll-cause mortality

COPERNICUS


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COPERNICUS

MERIT-HF 11.0%

US Carvedilol Program 11.1%

CIBIS II 13.2%

BEST 16.6%

COPERNICUS 18.5%

Annual placebomortality rate

Beta Blockers


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Beta-Blockers

Carvedilol(target dose 25 mg twice daily)A multiple adrenergic inhibitor

(n = 1,511)

Metoprolol tartrate(target dose 50 mg twice daily)

A beta-1 blockade agent

(n = 1,518)

Endpoints (mean follow-up 58 months):

Primary 1) All-cause mortality and 2) All-cause mortality or all-causehospitalization

Secondary Composite of all cause mortality or cardiovascular hospitalization;Composite of cardiovascular death, non-fatal acute MI, or heart transplantation;Worsening of heart failure; Cardiovascular death; NYHA class

3,029 patients with Class III-IV heart failureEnrolled at 317 centers in 15 European countries

COMET

Lancet 2003;362:7

Beta Blockers


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Beta Blockers

COMET Trial

Endpoint Carvedilol(n=1511)

Metoprolol(n=1518)

HR P

# Deaths 512 (34%) 600 (40%) 0.83 0.001

AnnualMortality

8.3% 10.0%

Mortality/Hospitalization

74% 76% 0.94 0.122

Carvedilol 25 mg bid target dose 42 mg/day mean dose achievedMetoprolol 50 mg bid target dose 85 mg/day mean dose achieved

Beta Blockers


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Beta BlockersCase Discussion

When to stop BB during hospitalization? recent initiation or uptitration responsible for fluid overload

significant low BP or cardiogenic shock

When to start BB during hospitalization? IMPACT-HF Trial (n=363)

admitted for worsening HF and stabilized in preparation fordischarge

in-hospital initiation of carvedilol -vs-post-discharge (> 2 weeks) initiation of carvedilol at MD discretion

beta blocker use at 60 days was improved (91% vs 73%, p< 0.00

no significant increase in hypotension, bradycardia, or worsening mean LOS 5 days in both groups

tendency toward lower event rate

Gattis et al. JACC2004; 43:1534-4

Beta-blockers


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1999 Guideline Dosing - Start low and go slow approach

2005 Guideline

To be announced

Beta blockersHFSA Guideline Highlights (continued)

Beta-blockers


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HFSA Guideline Highlights (continued)

1999 Guideline No specific recommendation regarding special populations

2005 Guideline To be announced


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Angiotensin II Receptor Blockers

ACE Inhibitors


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ACE InhibitorsMechanism of Action

VASOCONSTRICTION VASODILITATIONALDOSTERONE PROSTAGLANDINSVASOPRESSIN

SYMPATHETIC

ANGIOTENSIN II

BRADYKININ

ACE Kininase IIInhibitor

Inactive Fragments

Angiotensinogen

Angiotensin I

RENIN

ACE I hibit


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ACE InhibitorsV-HeFT II

NEJM 1987;316:1429. NEJM 1991;325:303. NEJM 1991;325:293. NEJM 1992;327:

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 1 2 3 4 5 6 7 8 9 10 11

Months

CumulativeProbabilityofDeath Placebo

Enalapril

CONSENSUS

p=0.016

*

p=0.001*

0

10

20

30

40

50

60

70

0 6 12 18 24 30 36 42 48

Months

Events%

Placebo

Enalapril

SOLVD-T

P=0.3*

0

5

10

15

20

25

30

35

40

45

50

0 6 12 18 24 30 36 42 48

Months of Follow-up

%E

vents

Placebo

Enalapril

SOLVD-P

p


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ACE Inhibitors

ATLAS Trial Target doses in previous clinical trials

enalapril 10 mg BID, lisinopril 20 mg daily,captopril 50 mg TID

Study subjects (n=3,164 pts)

NYHA class II-IV, LVEF < 30%

Comparison

lisinopril low 2.5-5 mg qd vs high 32.5-35 mg qd

follow-up - 46 months (median)

primary endpoint - all-cause mortality

Circulation 1999;100:2312


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ACE Inhibitors

Outcome Low-Dose

(n=1596)

Hi h-Dose

(n=1568)

RRR P value

Mortality 44.9% 42.5% 8% 0.128

CV mortality 40.2% 37.2% 10% 0.073

Mortality/hosp 83.8% 79.7% 12% 0.002

Mortality/HF hosp 74.1% 71.1% 8% 0.036

Mortality/CV hosp 60.4% 55.1% 15%


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ACE Inhibitors

Is obtaining target dose important?

Ramipril 5 mg po bid Enalapril 10 mg po bid

Lisinopril 40 mg po qd

Is it truly an ACE inhibitor cough? consider fluid, optimize diuretic dose

Are there reasons not to consider an ARB? Hypotension, hyperkalemia, renal dysfunction

Are there reasons to consider an ARB? Intolerable cough, angioedema (caution)

Do target doses need to be reach prior to initiatingbeta blocker therapy?



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Angiotensin II Receptor BlockersMechanism of Action

AT1 AT2

Vasoconstriction Proliferation Vasocondilation Anti-proliferatio

RECEPTORS

ANGIOTENSIN I

ANGIOTENSIN II

AT1RECEPTORBLOCKERS

ACEAlternative paths

Angiotensinogen

RENIN

A i t i II R t Bl k


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Angiotensin II Receptor BlockersCase Discussion

When should ARBs be used in lieu of ACEIs?

When should ARBs be used in addition to ACEIs?



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g p

Valsartan (Diovan) Val-HeFT Trial add on to ACEI therapy in HF (35% BB)

valsartan 160 mg bid reduced in hospitalizations

combo of BB/ACEI/ARB worse?

Candesartan (Atacand) CHARM Trial three trials with candesartan 32 mg qd

ALTERNATIVE - ARB safe in ACEI intolerant patient

ADDEDACEI/ARB/BB combination safe

PRESERVED - trend toward benefit

Valsartan (Diovan) VALIANT Trial post MI with clinical/radiological sx HF

valsartan 160 mg bid equivalent to captopril 50 mg tid

combo ACEI/ARB associated with additional ADEs

NEJM2001; 345:1667-75 Lancet2003; 362:759-66 NEJM2003; 349:1893-9

ACE Inhibitors and ARBs


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HFSA Guideline


ACEIs, rather than ARBs, are drugs of choice for patients with LVSwith or without symptoms of HF

In patients who are intolerant, consider the combination ofhydralazine/ISDN or ARB



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Digoxin

Digoxin


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Digoxin

Digoxin

(n=3397)

Placebo

(n=3403)

RRR P valu

Cause of Death

A ll 34.8% 35.1% NS 0.80

CV 29.9% 29.5% NS 0.78

Prog HF 11.6% 13.2% 12% 0.06Reason fo r Hosp italizat ion

A ll 64.3% 67.1% 8% 0.006

CV 49.9% 54.4% 13%


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gHFSA Guideline


Digoxin should be considered if systolic dysfunction (LVEF 40%),symptomatic HF (NYHAc II-III (A), NYHAc IV (C)), std therapy

Digoxin should be routinely administered to the majority of patients

at a dose of 0.125-0.25 mg daily

Rationale RADIANCE 1.2ng/mL, DIG Trial 0.8ng/mL

PROVED/RADIANCE retrospective, cohort analysis


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Digoxin

RADIANCE & PROVED Trials

Patients stabilized on digoxin, ACE-I, and diuretics

Worsening of HF, exercise tolerance, worsening NYHAclass, QOL, LVEF with withdraw of digoxin

DIG Trials

Patients randomized to digoxin or placebo

No reduction in mortality

Significant reduction in hospitalizations

J Am Coll Cardiol 1993;22:955. NEJM 1993;329:1. NEJM 1997;336:5

Digoxin


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Association of Outcomes and Concentration

JAMA 2003; 289:87


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Aldosterone Antagonists



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Collagen

deposition

Collagen

deposition

Fibrosis- myocardium

- vessels

ALDOSTERONE

Retention Na+

Retention H2O

Excretion K+

Excretion Mg2+

Edema

Arrhythmia

SpironolactoneCompetitive antagonist of theAldosterone receptor(myocardium, arterial walls, kidney)



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Case Discussion

When should an aldosterone antagonist beconsidered?

What are the relative contraindications?

What monitoring is important?

RALES Trial


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Study subjects (n=1,663) severe HF, NYHA class IV currently or w/in 6 mos serum potassium < 5.0 mmol/L, serum creatinine < 2.5 mg/dL

Comparison spironolactone 12.5-25 mg daily vs placebo follow-up - 24 months (mean) primary endpoint - all-cause mortality

Placebo(n=841) Diuretic(n=822) RRR P value

MortalityCV Mortality

- Prog HF-

SCD

46%37%22%

13%

35%27%16%

10%

30%31%36%

29%


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Placebon=3,319

1,012 Deaths

Randomize 3-14 DaysPost-AMI

Eplerenone25-50 mg QD

n=3,313

AMI, RALES, LVEF 40%, Standard Therapy

Primary endpoints: All-cause mortality CV mortality + CV hospitalization

Secondary endpoints: CV mortality CV hospitalization All-cause mortality + all-causehospitalization

Other endpoints: New onset of atrial fibrillation/flutter

NYHA functional class QOL

AMI=acute myocardial infarction; QOL=quality of life.Reproduced with permission: Pitt B, et al. Cardiovasc Drugs Ther2001;15:79-87.

EPHESUSM t lit R lt


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Mortality Results

Months since randomization

Cumulati

veincidence(%)

22

16

10

4

36271890

Placebo

Eplerenone

RR=0.85 (95% CI, 0.75-0.96)P=0.008

Pitt B et al. NEJM2003;348:1309-1321



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Spironolactone (Aldactone) - RALES Trial

recent or current NYHAc IVbeta blocker use 10%

initial dose 25 mg qd, mean dose 27 mg/d

Eplerenone (Inspra) - EPHESUS Trial

post-MI LVEF < 40% and rales initial dose 25 mg, mean dose 43 mg/d

Pitt B et al. NEJM1999; 341:709-17, Pitt B et al. NEJM2003; 348:1309-1



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HFSA Guideline

1999 Guideline 1 Recommendation

Spironolactone should be considered in patients withsevere HF due to LVSD


Role of the RAAS and NPS


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Role of the RAAS and NPS

Angiotensinogen

Angiotensin I

Angiotensin II

AII Receptor/Aldosterone

Renin

ACE

Kininogen

Kinins

Bradykinin

InactiveMetabolites

Kallikrein

Pro ANP, BNP

ANPBNP

CNP

Inactive

Metabolites

NEP

Natriuretic Peptides


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p

RAA System

Vasoconstriction

Sodium retention

Increased aldosteronerelease

Increased cellular growth

Increased sympathethicnervous system activity

NP System

Vasodilation

Sodium excretion

Decreased aldosteronerelease

Decreased cellular growth

Inhibition of sympatheticnervous system activity

Physiologic Effects

Released in response to ventricular stretch/volume overload Used as a marker of presence/severity of systolic dysfunctio

Efficacy Trial Hemodynamic Outcom


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Abraham WT et al. J Cardiac Failure 1998;4:37

-60

-40

-20

0

20

40

60

HR RAP PCWP SVR CI SVI

Placebo (n = 4)

Nesiritide (n = 10)

Changefromb

aseline(%

)

**

+

+

* p


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0 10 20 30 40 50

Dyspnea

Peripheral Circulation

Edema

Fatigue

Appetite

Percent Improved

Placebo (n = 42) Nesiritide 0.015 (n = 43) Nesiritide 0.030 (n =

p = 0.017

p < 0.001

p = 0.028

p = 0.271

p < 0.00

Colucci, et al. New Engl J Med2000; 343:246-53

PRECEDENT Trial


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Dobutamine (n = 83)

Nesiritide 0.015 mcg/kg/min (n =

Nesritide 0.030 mcg/kg/min (n =

p < 0.001

-60

-40

-20

020

40

60

80

Change from

Baseline in

Events/24 hours

Couplets Triplets V-Tach

p < 0.001

p = 0.001

Burger AJ, et al. Am Heart J2002; 144 (6): 1102

Inotropic Therapy in ADHF


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p py

Concerns with use

limited evidence suggesting benefit small trials, not randomized or placebo controlled

subjective endpoints

growing evidence suggesting harm PROMISE, OPTIME, ADHERE registry and others

Limited indications cardiogenic shock

bridge to transplantation

palliative care

OPTIME Trial


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Adverse event 12.6% ** 2.1%

Sustained hypotension 10.7% ** 3.2%

Acute MI 1.5% 0.4%

Atrial fibrillation (new onset) 4.6% * 1.5%

Death (60-day) 10.3% 8.9%Death (in-hospital) 3.8% 2.3%

Rehospitalization or death 35.0% 35.3%

Median cumulative hospital days 7 6

for CV cause within 60 days of

randomization (primary endpoint)

Cuffe MS et al. JAMA. 2002;287:15411547* p = 0.004**p < 0.001

Milrinone(n = 477)

Control(n = 472)

Implantable Defibrillators (MADIT II)


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Inclusion criteria MI > 1 month prior

LVEF < 0.30

No inducible arrhythmias

No coronary revascularization within 3 months

Average follow-up was 20 months

DefibrillatorGroup

(n = 742)

ConventionalTherapy(n = 490)

Mortalityp = 0.016

14.2% 19.8%

Moss AJ et al. NEJM2002; 346:877-8

Implantable Cardiac Defibrillators


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Mechanical Support


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Intra-aortic balloon pump (IABP)

used as bridge to TP or myocardial ischemia placed into high descending thoracic aorta

balloon counterpulsation

inflates during diastole - coronary perfusion deflates w/ aortic valve opening - arterial impedence

Left ventricular assist device (LVAD) extracorporeal vs implantable

allows ambulation and even discharge

operative mortality 10-15%

requires continuous anticoagulation

Intra-aortic balloon pump Left ventricular assist device


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Potential Future Agents


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Vasopressin Receptor Antagonists

Conivaptan (V1a/V2 antagonist) Phase 2 trials Tolvaptan (V2 antagonist) Phase 3 trials

ACTIV in CHF trial JAMA 2004; 291: 1963-1971.

EVEREST Trial ongoing

Calcium Sensitizers Levosimendan Calcium sensitization of contractile proteins

Binding site in the N-terminal domain of troponin C

Exerts both inotropic and vasodilatory effects

LIDO Study - significant reduction in mortality at 180 day REVIVE and SURVIVE Trials ongoing

Transplantation


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Current waiting list

candidates 88,523 (as of 6/6/05, 10:35 am) transplants 2005 4,375 (as of 5/27/05)

donors 2005 - 2,263 (as of 5/27/05)

Average waiting time - greater than 6 months

Only about one in five approved potential recipientsreceive a heart before succumbing to their disease

Another large percentage of patients rejected fromconsideration because of age, concurrent illness,

psychosocial factors

Documents

Update on the Management of CHF