Congestive Heart Failure: Strategic vs. Tactical Approaches while in the Trenches

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Congestive Heart FailureStrategic vs. Tactical
Approaches while in the Trenches
Alan Kono, MD FACC Cardiology Dartmouth-Hitchcock
Medical Center
2
Faculty Disclosure

• I have no financial relationships with vendors
• Even if I do own stock in said vendors, Ive lost
  whatever I put in
• I live pay check to pay check

• I am not prejudiced towards minorities
• I am not prejudiced towards religion
• I am not prejudiced towards gender

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(No Transcript)
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What do you see?
A Approaching the Bermuda Triangle
B Husseins Oil Fields Burning
C Armageddon
D Not sure, give me more info
Hurricane Isabel September 2003
5
What are you thinking?
A Go to Warp Factor 3, Scotty
-Captain Kirks view
B Now what did I do to deserve this?
-Catholic view
C Oh Shit
-Buddhist view
D Not sure, give me more info
-Agnostic view
I see some really good surfing weather Alan
Kono, surfing dude
6
Audience Disclosure

• Choose one of the Following
• I grew up singing the songs of
• Joan Baez
• Peter, Paul, and Mary
• Doobie Brothers
• Blink 182
• Who are these people?

7
CHF OVERVIEW

• Demographics
• Pathophysiology
• Therapy
• Delivery of Care
• Strategic vs. Tactical approaches

8
Strategic vs. Tactical

• Strategic- of pertaining tolarge scale planning
  and directing of operations in adjustments to
  combat areas
• Tactical- of pertaining to technique or science
  of securing objectives designated by strategy
  clever or adroit maneuvers

Websters New Collegiate Dictionary American
Heritage Dictionary
9
CHF OVERVIEW

• Demographics
• Pathophysiology
• Therapy
• Delivery of Care
• Strategic vs. Tactical approaches

10
Heart Failure

• A clinical syndrome in which the heart is
• unable to pump sufficient blood to meet
• the metabolic demands of the body.

11
Heart Failure

• Approximately 5 million Americans have CHF (male
  to female ratio 11)
• 550,000 new cases annually
• Incidence of 10/1000 gt 65 years of age
• Hospital discharges 1,000,000 (2001)
• Single largest expense for Medicare
• Five-year mortality rate as high as 50

AHA. 2001 Heart and Stroke Statistical Update
12
CHF Patient Population by NYHA Class
Class I No limitations of physical
activity Class II Slight limitations of physical
activity Class III Marked limitations of
physical activity Class IV Inability to carry
out physical activities without discomfort
and/or symptoms at rest
Class IV 240 K (5)
Class I 1.68 M (35)
Class III 1.20 M (25)
Class II 1.68 M (35)
AHA Heart and Stroke Statistical Update 2001
13
New Approach to the Classification of Heart
Failure
Hunt SA et al. J Am Coll Cardiol.
20013821012113.
14
Classification of HF Comparison Between ACC/AHA
HF Stage and NYHA Functional Class
ACC/AHA HF Stage1
NYHA Functional Class2
None
A At high risk for heart failure but
without structural heart disease or symptoms of
heart failure (eg, patients with hypertension or
coronary artery disease)
I Asymptomatic
B Structural heart disease but without symptoms
of heart failure
C Structural heart disease with prior or current
symptoms of heart failure
II Symptomatic with moderate exertion
III Symptomatic with minimal exertion
IV Symptomatic at rest
D Refractory heart failure requiring specialized
interventions
1Hunt SA et al. J Am Coll Cardiol.
20013821012113. 2New York Heart
Association/Little Brown and Company, 1964.
Adapted from Farrell MH et al. JAMA.
2002287890897.
15
Historical Perspective

• Hemodynamic model
• Preload
• Afterload
• Contractility

• Neurohormonal model

Remodeling model
16
Historical Perspective

• 1985-Digitalis and Diuretics are the
  mainstay of therapy improve symptoms
• To date, none of the drugs available have
  been shown to reduce mortality.
• Patients at high risk for failure should be
  treated before CHF becomes manifest.
• Large studies are needed for
• Prevention trials
• Treatment trials

Furberg, Yusuf. Am J Cardiology 55 1985
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Etiology and Clinical Characteristics of Heart
Failure

• Coronary artery disease is the most common
  etiology of heart failure1
• 75 of CHF cases have antecedent hypertension2
• Signs and symptoms of congestion (eg, rales,
  dyspnea, etc) are not always evident in HF
  patients
• Most deaths occur suddenly and unexpectedly
  despite apparent clinical compensation2

1Steering Committee and Membership of the
Advisory Council to Improve Outcomes Nationwide
in Heart Failure. Am J Cardiol. 199983(suppl
2A)1A39A. 2AHA. 2001 Heart and Stroke
Statistical Update. 2000.
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Risk Factors for Heart Failure

• Diabetes
• Congenital heart defects
• Other
• Obesity
• Age
• Smoking
• High or low hematocrit level
• Obstructive Sleep Apnea

• CAD or history of MI
• Hypertension
• Valvular heart disease
• Alcoholism

CADcoronary artery disease LVHleft ventricular
hypertrophy.
19
CHF OVERVIEW

• Demographics
• Pathophysiology
• Therapy
• Delivery of Care
• Strategic vs. Tactical approaches

20
Myocardial Injury
21
CAD
VHD
HTN
VIRAL
22
Pathophysiologic Effectsof Compensatory
Mechanismsin Heart Failure
As ventricular function deteriorates, the heart
relies on a variety of adaptive mechanisms to
help maintain adequate cardiac output

• Frank-Starling Law of the Heart
• Renin-angiotensin-aldosterone system
• Sympathetic nervous system

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Compensatory MechanismsFrank-Starling Law
Maximal
Normal LV
Mild LVD
Stroke Volume
Normal Resting
Severe LVD
Low-Output Symptoms
Normal Resting
Pulmonary Edema Congestive Symptoms
Left Ventricular End-Diastolic Pressure
24
Compensatory MechanismsRenin-Angiotensin-Aldoste
rone System

• Beta
• Stimulation
• CO
• Na

Renin Angiotensinogen
Angiotensin I
ACE
Angiotensin II
Kaliuresis
Fibrosis
Aldosterone Secretion
Peripheral Vasoconstriction
Salt Water Retention

• Plasma Volume

Edema

• Afterload

• Preload

• Cardiac Output

• Cardiac Workload

Heart Failure
25
Neurohormonal Activation in Heart Failure
Myocardial injury to the heart (CAD, HTN, MCP,
Valvular disease)
Initial fall in LV performance, wall stress
Activation of RAS and SNS
Fibrosis, apoptosis,hypertrophy,
cellular/molecular alterations,myotoxicity
Peripheral vasoconstriction Hemodynamic
alterations
Remodeling and progressive worsening of LV
function
Heart failure symptoms
Morbidity and mortality Arrhythmias Pump failure
FatigueActivity altered Chest
congestionEdemaShortness of breath
RAS, renin-angiotensin system SNS, sympathetic
nervous system.
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SNS Activation Leads Directly to Impaired Cardiac
Function
? CNS sympathetic outflow
? Sympathetic activity tokidneys blood vessels
? Cardiac sympathetic activity
?1- receptors
?2- receptors
?1- receptors
Activation of RAS
Vasoconstriction Sodium retention
Myocyte hypertrophy, dilation,ischemia,
arrhythmias, death
Disease progression
Adapted from Packer M. Prog Cardiovasc Dis.
199839(suppl I)3952.
27
Myocardial Injury
28
Remodeling
Chamber Enlargement
29
RemodelingPrognosis-Volume
Gaasch, et al CPC 1995
30
CHF OVERVIEW

• Demographics
• Pathophysiology
• Therapy
• Delivery of Care
• Strategic vs. Tactical approaches

31
The following therapies have been shown to
improve mortality in CHF

• Digoxin
• ACE inhibitors
• Angiotensin Receptor Blockers
• Calcium Channel Blockers
• B-blockers
• Loop Diuretics

32
CHF THERAPY
ACE-Inhibitors B-blockers
33
Pathogenesis andTherapeutic Approaches

• LV Function

Digoxin
Vasodilators ACE Inhibitors

• Cardiac Output

• Imepdance

ACE Inhibitor
RAA System ANF Catecholamines

Neurohormone Activation
Salt and Water Retention
Diuretics
B-blockers
Progressive Heart Failure
34
ACE InhibitorsMechanism of Action
Angiotensinogen
Renin
Angiotensin I
Bradykinin
ACE Inhibitor
ACE
Kinase II
X
X
Inactive Kinins
Angiotensin II
??Prostaglandins

• Aldosterone

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Effect of ACE Inhibitors on Mortality Reduction
in Patients With CHF
Mortality
Trial
ACEI
Controls
RR (95 CI)
Chronic CHF
CONSENSUS I
39
54
0.56 (0.340.91)
SOLVD (Treatment)
40
35
0.82 (0.700.97)
SOLVD (Prevention)
15
16
0.92 (0.791.08)
Post MI
SAVE
25
20
0.81 (0.680.97)
AIRE
17
23
0.73 (0.600.89)
TRACE
0.78 (0.670.91)
35
42
SMILE
6.5
8.3
0.78 (0.521.12)
Average
21
25
Garg R et al. JAMA. 199527314501456. Data
shown from individual trialsnot direct
comparison data.
36
ACE Inhibitors Proven to Reduce Morbidity and
Mortality

• ?7000 patients evaluated in long-term
  placebo-controlled clinical trials
• Improvements in cardiac function, symptoms, and
  clinical status equivocal effects on exercise
  tolerance
• ? all-cause mortality by 23 (Plt.001) and ?
  combined risk of death and hospitalization by 35
  (Plt.001)
• Effect shown in SOLVD Treatment, CONSENSUS, and
  V-HeFT II trials

Garg R, Yusuf S. JAMA. 199527314501456.
37
ACE Inhibition in Heart Failure
Consensus Recommendations

• All patients with heart failure due to left
  ventricular systolic dysfunction should receive
  an ACE inhibitor unless they have a
  contraindication to its use or cannot tolerate
  treatment with the drug.
• Treatment with an ACE inhibitor should not be
  delayed until the patient is found to be
  resistant to treatment with other drugs.

Steering Committee and Membership of the Advisory
Council to Improve Outcomes Nationwide in Heart
Failure. Am J Cardiol. 199983(suppl 2A)1A39A.
38
Angiotensin II

• One of the most potent pressor agents known.
• Produced by conversion of angiotensin I by ACE
  (and alternative pathways).
• Overall increase in systemic blood pressure
  results from A-II synergistic effects on various
  systems.
• Inhibits the release of renin.
• Increases the secretion of aldosterone.

39
PATHOPHYSIOLOGIC ROLE OF ANGIOTENSIN II
Aldosterone Production
Vasoconstriction
Cell Growth
? Sodium/Water Retention
???PVR
LVH Vascular Remodeling
???BP
? BP
Hypertension. Feb. 199423(2)258
40
ARBAngiotensin Receptor Blockers

• This-a-sartan and that-a-sartan?

41
Elite II
Primary All Cause Mortality
1.0 0.8
Survival Rate
of Events
Captopril250 Losartan 280
Hazards Ratio(95) 0.88 (.75,1.05) p
0.16 mortality rate 11
0 100 200 300 400
500 600 700
Presented at the AHA, Atlanta 1999 by B.Pitt M.D.

Days of Follow Up
42
Effect of Valsartan on Mortality by ACE
Inhibitor/?-Blocker Subgroups (Val-HeFT)
Favors valsartan
Favors placebo
n
Not Receiving ACEI
366
Receiving ACEI
4,644
Receiving ACEI without ?-Blockade
3,034
Receiving ACEI and ?-Blockade
1,610
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
Relative Risk (95 CI)
Data presented at FDA Cardio-Renal Advisory
Panel.Adapted from Cohn JN et al. N Engl J Med.
200134516671675.
HF NOT AN APPROVED INDICATION FOR VALSARTAN
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ACC/AHA Guidelines on the Role of ARBs in HF

• Several clinical trials with ARBs failed to show
• mortality benefit in heart failure
• ARBs should not be considered equivalent or
  superior to ACE inhibitors in the treatment of
  HF
• ARBs should not be used for the treatment of HF
  in patients who have had no prior use of an ACE
  inhibitor
• ?-Blockers, rather than ARBs, should be added to
  therapy for patients with HF who are taking an
  ACE inhibitor until further data are available

Hunt SA et al. J Am Coll Cardiol.
20013821012113.
44
CHARM Trial

• Candesartan in Heart Failure Assessment of
  Reduction in Mortality and Morbidity
• CHARM Alternative
• CHARM Added
• CHARM Preserved

Lancet 362 759-776 September 2003
45
CHARM
Lancet 362 759-776 September 2003
46
VALIANT

• Valsartan, Captopril or Both in MI complicated by
  Heart Failure, LV dysfunction or Both
• EFlt35 (echo or LV gram) lt40 (MUGA)
• 14,808 pts enrolled
• No significant difference in
• Cardiovascular Death
• Combined Cardiovascular endpoints
• Valsartan showed non-inferiority

Pfeffer. NEJM 359 (20) 11/03
47
VALIANT
Pfeffer. NEJM 359 (20) 11/03
48
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49
B-Blockers in CHFHistorical Perspective

• 1975- 1980 First reports of clinical benefit
• High NE associated with high mortality
• B receptor down-regulation
• ?Are B-Adrenergic-blocking agents useful in the
  treatment of DCM

Waagstein Br Heart Journal 1975, Swedberg Br
Heart Journal 1980
Alderman Grossman Circulation 1985
50
B-Blockers in CHF

• Are B-Blockers effective in CHF?
• Is it a class effect?
• Is it safe to use in advanced CHF (FTC IV)?
• When should you initiate B-blockers?
• Are B-blockers safe to use post MI CHF?

-Yes ( thats what the experts say) -No (they
didnt teach that to me in my training)
-Yes (a B-blocker is a B-blocker) -No
(Designer Drugs are cool)
-Yes, the bookies have the odds -No, its
better in less severe patients
-In the ER -In the Hospital -In the Clinic
-Yes, Im feeling lucky -No, youre pulling my leg
51
ß-Blockers Use in Heart Failure is Now
Supported by Overwhelming Evidence

• gt15,000 patients evaluated in long-term
  placebo-controlled clinical trials
• Improvement in cardiac function and symptoms
  equivocal effects on exercise tolerance
• Decrease in all-cause mortality by 3065
  (Plt.0001)
• Decrease in combined risk of death and
  hospitalization by 3540 (Plt.001)
• Effect shown in patients already receiving ACE
  inhibitors

52
Selectivity of ?-Blocking Agents
MI, HTN, DM, Insulin Resistance
Sympathetic Activation
?1 receptors
?2 receptors
?1 receptors
?1 selectiveblockade
? non-selectiveblockade
?1, ?2, ?1blockade
Cardiotoxicity
53
Major Placebo Controlled Trials of Beta-Blockade
in Heart Failure
Target Mean Dosage HF Patients Follow-up D
osage Achieved Effects on Study Drug Severity (n)
(yrs) (mg) (mg/day) Outcomes CIBIS bisoprolo
l moderate/ 641 1.9 5 qd 3.8 All-cause
mortality Circ. 1994 severe NS CIBIS-II3
bisoprolol moderate/ 2647 1.3 10
qd 7.5 All-cause mortality Lancet 1999
severe ?34 (Plt.0001) MDC metoprolol mild/
383 1 200 qd 108 Death or need for Lancet 1993
tartrate moderate transplant
(primary endpoint)NS MERIT-HF1 metoprolol
mild/ 3991 1 200 qd 159 All-cause
mortality Lancet 1999 succinate moderate
?34 (P.0062) BEST4 bucindolol
moderate/ 2708 2 50-100 152 All-cause
mortality NEJM 2001 severe bid NS US
Carvedilol2 carvedilol mild/ 1094 6.5 6.25
to 50 45 All-cause mortality NEJM 1996
moderate months bid ?65 (P.0001) COPERNICU
S5 carvedilol severe 2289 10.4 25
bid 37 All-cause mortality NEJM 2001
months ? 35 (P .0014)
NOT AN APPROVED INDICATION METOPROLOL
SUCCINATE NOT APPROVED FOR SEVERE HF OR FOR
MORTALITY REDUCTION ALONE
Not a planned end point.
54
Effect of Carvedilol on Disease Progression in
Mild or Moderate Heart Failure
1.0
Carvedilol (n232)
0.8
Probability of event-free survival?
Risk reduction 48
Placebo (n134)
P.008
0.6
0
0
50
100
150
200
250
300
350
400
Days
Disease progression was defined as HF death or
hospitalization or the need for sustained
increase in medications for HF.Patients were on
a background of diuretics, ACE inhibitors,
digoxin. Colucci WS et al. Circulation.
19969428002806.
55
Study Results
56
Total Mortality
20
15
10
Percent of patients
5
0
0
3
6
9
12
15
18
21
Months of follow-up
57
?-Blockers in Class IV Heart Failure
Proportion of patients with class IV heart failure
US Carvedilol Program1 3 MERIT-HF2
4(Metoprolol succinate) CIBIS
II3 16 (Bisoprolol) BEST4 8 (Bucindolol)
HF not an approved indication. 1Packer M. N Engl
J Med. 199633413491355. 2MERIT-HF Study
Group. Lancet. 199935320012007. 3CIBIS II
Investigators. Lancet. 1999353913.4The BEST
Investigators. N Engl J Med. 200134416591667.
58
COPERNICUS
All-Cause Mortality
100
90
Carvedilol
80
Survival
Placebo
70
35 ? in risk P.00013 (unadjusted)P.0014
(adjusted)
60
0
Packer M et al. N Engl J Med. 200134416511658.
59
COMET

• More than 3000 patients with class IIIV heart
  failure due to ischemic or nonischemic
  cardiomyopathy
• Randomized to carvedilol or metoprolol tartrate
  (in addition to usual therapy) for over 3 years
• Prespecified end points all-cause mortality,
  combined risk of all-cause mortality and
  hospitalization
• Results expected 2003

Lancet 362 (9377) 7-13, July 2003
NYHA CLASS IV HF NOT APPROVED USE FOR ANY
?-BLOCKER HF NOT AN APPROVED INDICATION FOR
METOPROLOL TARTRATE
Carvedilol or Metoprolol European Trial
60
COMET Study Design
3029 patients with stable heart failure, New York
Heart Association Class II-IV, receiving standard
treatment including ACE inhibitors
(n?1500) Metoprolol 50 mg bid
Randomized (No run-in phase)
(n?1500) Carvedilol 25 mg bid
Time to 1020 deaths Estimated to be 4 to 6 years
Screening
Titration to maximum tolerated or target
dose (Start carvedilol 3.125 mg bid, metoprolol
tartrate 5 mg bid)
Assessments every four months during maintenance
phase
Poole-Wilson PA et al. Eur J Heart Fail
20024321-329.
61
Baseline Characteristics
n number of patients SD standard deviation
IHD ischemic heart diseaseHF heart failure
bpm beats per minute AF  atrial fibrillation.
Poole-Wilson PA et al. Lancet 20033627-13.
62
Baseline Characteristics
Concomitant Medication at Randomization
Stopped before study start ACE angiotensin
converting enzyme ARB angiotensin receptor
blocker.
Poole-Wilson PA et al. Lancet 20033627-13.
63
Results - Primary Endpoints
95 CI
P
Hazard Ratio
Metoprolol
Carvedilol
Primary endpoints
0.0017
0.74, 0.93
0.83
600/1518 40
512/1511 34
Mortality
0.0004
0.70, 0.90
0.80
534/1518 35
438/1511 29
Cardiovascular Mortality
0.122
0.86, 1.02
1160/1518 76
1116/1511 74
Mortality and all cause hosp.
0.94
CI Confidence Interval
Poole-Wilson PA et al. Lancet 20033627-13.
64
Primary Endpoint of Mortality
40
Metoprolol
30
Percent Mortality ()
20
Carvedilol
Hazard ratio 0.83, 95 CI 0.74-0.93, P 0.0017
10
0
0
1
2
3
4
5
Time (years)
Number at risk Carvedilol 1511
1366 1259 1155 1002 383 Metoprolol
1518 1359 1234 1105 933 352
Poole-Wilson PA et al. Lancet 20033627-13.
65
COMET Mortality in Subgroups
Carvedilol Metoprolol
n n
Gender
male
1200 1217
female
311 301
Age
lt65
834 803
gt65
677 715
NYHA
II
730 736
III
732 716
IV
49 66
Etiology
Other
735 703
IHD
776 815
LVEF
lt 25
706 630
gt 25
743 819
Heart rate
lt 80
693 733
gt 80
816 783
Systolic BP
lt 110
245 235
110-139
817 849
gt 140
447 434
Diabetes
yes
360 371
no
1150 1143
Overall
1511 1518
Metoprolol better
Carvedilol better
0.50
0.75
1.00
1.25
1.50
Poole-Wilson PA et al. Lancet 20033627-13.
66
COMET Median Survival

• Carvedilol - 8.0 years
• Metoprolol Tartrate - 6.6 years
• Carvedilol prolonged median survival by 1.4 years
  (95 CI 0.5 - 2.3)
• Assuming constant hazard

CI confidence interval.
Poole-Wilson PA et al. Lancet 20033627-13.
67
Change in Heart Rate
90
Error bars represent 1 standard error
80
Metoprolol
P 0.0022 P 0.0034 P 0.0040
Heart rate (beats.min-1)
Carvedilol
75
70



60
0
1
2
3
4
5
Time (years)
Poole-Wilson PA et al. Lancet 20033627-13.
68
Adverse Events
N number of patients AE adverse event CV
cardiovascular.
Poole-Wilson PA et al. Lancet 20033627-13.
69
Adverse Events
N number of patients AE adverse event.
Poole-Wilson PA et al. Lancet 20033627-13.
70
Withdrawal Rates
N number of patients.
Poole-Wilson PA et al. Lancet 20033627-13.
71
Degree of b1-Blockade Can Be Assessed by
Inhibition of Exercise-Induced Tachycardia
25
20
15
? in Exercise HR
10
5
0
20
40
60
80
100
0
b1-Receptor Occupancy

Modified from deMey et al., Br J Clin Pharmacol
1994 38 480-3
72
Carvedilol and Metoprolol Produce Similar
b1-Blockade When Given in 21 Dose Ratio
X axis shows total daily doses (mg)
Change in Exercise Heart Rate
Metoprolol
Carvedilol
Data shown not from direct comparative trials
Metoprolol IR 50 100
200 300 400 Carvedilol
25 50 100
150 200

Data from 9 carvedilol and 27 metoprolol
tartrate studies. Data on File, GlaxoSmithKline.
Courtesy, Dr. Milton Packer
73
Effect of b-Blockers on Exercise Heart Rate in
Patients With Chronic Heart Failure
-40
X axis shows total daily doses (mg)
b-1 receptor down-regulation
-30
No CHF
Change in Exercise Heart Rate
-20
CHF
-10
0
Metoprolol IR/XL 25 50 100
150 200 Carvedilol
12.5 25 50
75 100

Data derived from 12 trials of carvedilol or
metoprolol IR or XL alone or comparing the two.
Data on File, GlaxoSmithKline. Courtesy, Dr.
Milton Packer.
74
Dose Response Curves for b1-Blockade With
Metoprolol and Carvedilol in Heart Failure
Low dose subgroup ( lt 100 mg/day) in MERIT
High dose subgroup ( gt 100 mg/day) in MERIT
Change in Exercise Heart Rate
Metoprolol XL 25 50 75 100
150 200 Carvedilol 12.5 25 37.5
50 75 100

Wikstrand J et al. J Am Coll Cardiol
200240491-498.
75
MERIT-HF Effect of Dose on Survival Benefit
Metoprolol-XL 192 mg/day
Metoprolol-XL 76 mg/day
25
25
38 ? risk P0.010
38 ? risk P0.002
20
20
15
15
Placebo n1845
Placebo n1845
Mortality
10
10
Metoprolol XL n604
Metoprolol XL n1202
5
5
0
0
0
3
6
9
12
15
0
3
6
9
12
15

Months
Months
Wikstrand J et al. J Am Coll Cardiol
200240491-498.
76
Time Course of Plasma Levels of Metoprolol and
Carvedilol During 24-Hour Period
500
75
20 attenuation of exercise heart rate
400
50
300
Serum metoprolol (nmol/l)
Serum carvedilol (ng/ml)
200
25
100
0
0
6AM 12NO 6PM 12MN
6AM
Carvedilol 25 mg BID Metoprolol IR 50 mg BID
8 attenuation of exercise heart rate
1. Sandberg A et al. Eur J Clin Pharmacol 1988
33 SupplS9-S14. 2. de Mey C et al., Clin
Pharmacol Ther 1994 55 329-37 3. Cubeddu LX, et
al., Clin Pharmacol Ther 1987 41 31-44. 4.
Abrahamson et al., J Clin Pharmacol
199030S46-S54

77
?-Blocker Trials Intervening Within 24 Hours of
an Acute Myocardial Infarction
1Hjalmarson A et al. Lancet. 19812(8251)823827.
2The Miami Trial Research Group. Am J
Cardiol.198556(14)15G22G. 3First International
Study of Infarct Survival Collaborative Group.
Lancet. 19862(8498)5766.
78
Rationale for CAPRICORN

• ?-Blocker trials in acute myocardial infarction
  were conducted mostly during the 1970s and 1980s
• No thrombolysis or primary angioplasty
• Much less use of aspirin
• No ACE inhibitors
• Patients with heart failure were usually excluded
• Left ventricular function was not assessed
• Study populations were mostly lower risk

Dargie HJ et al. Eur J Heart Fail. 20002325332.
79
CAPRICORNAll-Cause Mortality
1.00
Carvedilol n975
0.90
Risk reduction

• 23
• (2, 40)

0.80
Proportion EvenPt-free
Placebo n984
0.70
P.031
0.60
0
0
0.5
1
1.5
2
2.5
Years
The CAPRICORN Investigators. Lancet.
200135713851390.
Mortality rates Placebo 15 Carvedilol 12
80
COPERNICUS Death, Hospitalization, or Withdrawal
During First 8 Weeks
20
15
n1133
Placebo
10
Patients With Event
Hazard ratio (95 confidence interval) 0.83
(0.681.03)
n1156
Carvedilol
5
0
0
2
4
6
8
Weeks
Weeks
Weeks
Weeks
A double-blind, randomized, placebo-controlled
study of 2289 euvolemic patients who had symptoms
of heart failure at rest or on minimal exertion
for at least 2 months and an ejection fraction of
lt25. Krum H et al. JAMA. 2003289712718.
Post Randomization

• At 2 weeks, 97 of patients were either receiving
  or titrated to 6.25 mg bid

81
B-Blockers in CHF

• Are B-Blockers Effective in CHF?
• Is it a class effect?
• Is it safe to use in advanced CHF (FTC IV)?
• When should you initiate B-blockers?
• Are B-blockers safe to use post MI CHF?

-Yes
-Effficacy seen with Bisoprolol, Metoprolol XL,
Carvedilol
-Efficacy and safety established with Carvedilol
-May be started in the hospital when euvolemic
(IMPACT-HF)
-May be initiated post MI with CHF/LV dysfunction
(CAPRICORN)
82
B-Blockers in CHFNew Paradigms

• May initiate early rather than late
• Start low, go slow
• Initiate in the hospital
• If on a B-blocker and decompensates
• Continue or reduce dosage
• Rarely discontinue

83
CHF THERAPY
Calcium Channel Blockers Digoxin Diuretics
84
PRAISE2
1652 patients with CHF of non-ischemic
etiology 10 mg amlodipine
HR 1.09
31.7
33.7
Presented at ACC Anaheim March 2000
85
Digoxin Use to Improve Symptoms and Clinical
Status

• DIG Trial
• 6800 patients followed over 3 years
• No benefit seen in overall mortality
• 34.8 with digoxin vs 35.1 with placebo (PNS)
• 28 significant decrease in CHF hospitalizations
  compared with placebo (Plt.001)

The Digitalis Investigation Group. N Engl J Med.
1996 335490498.
86
Digoxin Does NOT Decrease Mortality... but
decreases hospitalization (6)
Mortality ()
Months
Digitalis Investigation Group, N Engl J Med
1997336525-33
87
Randomized Trials of Loop Diuretics
88
Randomized Trials of Aldosterone Blocking
Diuretics

• RALES Trial
• EPHESUS Trial

89
Fluid Status-Goals

• Neck veins should be less than 5-7 cm of water
• Abdominal jugular reflux should be negative
• Eliminate peripheral edema
• Follow creatinine carefully while diuresing
  patient

90
Randomized AldactoneEvaluation Study (RALES)
1.00
0.95
0.90
0.85
0.80
0.75
Probability of Survival
0.70
Spironolactone
0.65
0.60
Plt.001
0.55
Placebo
0.50
0.45
0.00
0
3
6
9
12
15
18
21
24
27
30
33
36
Months
Pitt B., et al. N Engl J Med. 1999341709717.
NOT INDICATED TO REDUCE MORTALITY IN HF
91
EPHESUS Design
AMI, LVEF 40, Rales, Standard Therapy
Eplerenone 2550 mg qd n 3100
Placebon 3100
Randomize 314 Days PostAMI
1012 Deaths
Primary End Points Total mortality CV
mortality/CV hospitalization Secondary End
Points CV mortality Total mortality/total
hospitalizations
CV hospitalization hospitalization for heart
failure, MI, stroke, or ventricular arrhythmia
92
Relative Risk of Total Mortality
22
20
18
16
14
Placebo Eplerenone
Cumulative Incidence ()
12
10
RR 0.85 (95 CI, 0.75-0.96) P 0.008
8
6
4
2
0
36
33
30
27
24
21
18
15
12
9
6
3
0
Months Since Randomization
93
Selected Adverse Events
No. of Patients () Eplerenone n 3307 Placebo n 3301 P value
GI disorder 659 (19.9) 583 (17.7) 0.02
Menstrual disorder 0.4 0.4 1.0
Gynecomastia 12 (0.5) 14 (0.6) 0.70
Impotence 21 (0.9) 20 (0.9) 1.0
Respiratory disorders 729 (22.0) 803 (24.3) 0.03
Metabolic disorders 568 (17.2) 635 (19.2) 0.03
All patients who received at least one dose of
study drug were included in the safety analysis
Statistically significant
94
Effects on Potassium Homeostasis
4.7 absolute decreaseP lt 0.001
14
12
10
Eplerenone
Patients ()
8
1.6 absolute increase P 0.002
Placebo
6
4
2
0
Serious Hyperkalemia (K ? 6.0 mEq/L)
Hypokalemia (K ? 3.5 mEq/L)
95
EPHESUS Summary

• Eplerenone at a mean dose of 43 mg once daily
  reduced
• Total mortality 15 (P 0.008)
• CV mortality/CV hospitalization 13 (P 0.002)
• CV mortality 17 (P 0.005)
• Sudden cardiac death 21 (P 0.03)
• Total mortality/total hospitalization 8 (P
  0.02)
• Patients hospitalized for HF 15 (P 0.03),
  episodes of hospitalization for HF 23 (P 0.02)
• These effects were relatively consistent across
  pre-defined sub-groups

96
Lives saved by treating 1000 people

• Hope lt1
• SOLVD Prevention 7
• SOLVD Treatment 17
• MERIT 38
• CIBIS 42
• RALES 52
• COPERNICUS 70

97
Remodeling
Afterload Reduction
98
Remodeling
Therapy
99
Remodeling and Survival Effects by Drug Class
Established Rx Remodeling Effects Survival Effects
ACE-I Benefit Benefit
ARB Benefit (ACEI better) Benefit (ACEI better)
Aldo-B Benefit Benefit
Beta-B Benefit Benefit
Other Rx
Vasop-I Benefit (ACEI-neutral) Benefit (ACEI-neutral)
ET-1-B No Benefit No Benefit
TNFa-B No Benefit No Benefit
Ibopamine Adverse Adverse
100
CHF NEW THERAPIES
101
New Therapies

• Biventricular pacing-LV pacing via the coronary
  sinus
• TNF-alpha blockers- for Class III-IV CHF
• Endothelin blockers
• Neutral endopeptidase blockers
• Vasopressin

102
Biventricular PacingVentricular Dysynchrony

• Abnormal ventricular conduction resulting in a
  mechanical delay
• Wide QRS (IVCD) typically LBBB morphology
• Poor systolic function
• Impaired diastolic function

ECG depicting interventricular conduction delay
103
Wide QRS Proportional Mortality Increase
QRS Duration (msec)

• Vesnarinone Study1(VEST study analysis)
• NYHA Class II-IV patients
• 3,654 ECGs digitally scanned
• Age, creatinine, LVEF, heart rate, and QRS
  duration found to be independent predictors of
  mortality
• Relative risk of widest QRS group 5x greater
  than narrowest

lt90
90-120
120-170
170-220
gt220
Adapted from Gottipaty et al.
1 Gottipaty V, Krelis S, et al. ACC 1999
Abstr847-4.
104
Issues Associated with Heart Failure
Abnormal local wall strain
Dilated Cardiomyopathy (DCM)
Healthy
Longer
SEPTUM
SEPTUM
BASE
BASE
Relaxed
APEX
APEX
Shorter
Courtesy of D. Kass, MD, Johns Hopkins
University, Maryland.
105
Ventricular Dysynchrony
Click to Start/Stop
106
Etiology of Ventricular Dysynchrony

• What Causes Ventricular Dysynchrony?1
• Inter- or intraventricular conduction delays
  usually manifested as left bundle branch block
• Regional wall motion abnormalities with increased
  workload and stresscompromising ventricular
  mechanics
• Disruption of myocardial collagen matrix
  impairing electrical conduction and mechanical
  efficiency
• Estimated that 15 of all HF patients have
  ventricular dysynchrony2

1 Tavazzi L. Eur Heart J 2000211211-1214. 2
Shenkman et al. Circulation 2000 102(18)Suppl
II, abstract 2293.
107
Clinical Consequences of Ventricular Dysynchrony
Abnormal interventricular septal wall
motion Grines C, et al. (1989)
Reduced dP/dt Xiao H, et al. 1992
4-Chamber.avi
Reduced diastolic filling times Grines, et al.
(1989) Xiao, et al. (1991)
Prolonged MR duration Grines, et al.
(1989) Xiao, et al. (1991)
108
LV Reverse Remodeling after CRT
MR area
LV End Systolic and Diastolic Volumes
No pacing
Pacing
Pacing
No pacing
N 25
Yu CM, et al, Circulation. 2002105438-445.
109
Cardiac Resynchronization Therapy Effect on LV
Size and Function (MIRACLE)
Paired, Median Changes from Baseline
LVEDV
LVEF
MR Jet Area
? Control (n151) ? CRT (n172)
St. John Sutton M, et al. Circulation.
20031071985-1990.
Doug Smith
110
Effect of Beta Blocker Therapy
Paired, Median Changes from Baseline at 6 Months
LVEDV
LVEF
MR Jet Area
? Control ? CRT
p lt 0.05, CRT vs. Control within subgroups p
lt 0.05, CRT vs. CRT between subgroups
St. John Sutton M, et al. Circulation.
20031071985-1990.
Doug Smith
111
MIRACLE
NYHA class
www.FDALive.com. Circulatory systems devices
panel July 10, 2001.
112
MIRACLE
Exercise testing
www.FDALive.com. Circulatory systems devices
panel July 10, 2001.
113
MIRACLE
Echocardiography
www.FDALive.com. Circulatory systems devices
panel July 10, 2001.
114
COMPANION
Comparison of Medical Therapy, Pacing and
Defibrillation in Heart Failure
Hypothesis

• CRT with optimal pharmacologic therapy (OPT),
  alone or in combination with ICD backup, can
• Reduce all-cause hospitalization and mortality
• Reduce cardiac morbidity
• Increase total survival
• Improve exercise performance (sub-study)
• when compared to OPT alone

115
COMPANION
Study design

• Parallel, randomized

116
Bi-Ventricular Pacing Criteria for referral

• NYHA FTC III-IV CHF
• EFlt30-35
• QRS gt130ms (LBBBgtRBBB)
• Failing optimal medical Therapy
• Less data on patients with permanent pacers
• Less data on patients with Afib

117
CHF OVERVIEW

• Demographics
• Pathophysiology
• Therapy
• Delivery of Care
• Strategic vs. Tactical approaches

118
Approach to the Patient With Heart Failure
Assessment of LV function(echocardiogram,
radionuclide ventriculogram)
EF ?40
Assessment of fluid volume status
Signs and symptoms offluid retention
No signs and symptoms offluid retention
?
Diuretic(titrate to euvolemic state)
ACE inhibitor
Digoxin
Aldosterone Antagonist
B-Blocker
Adapted from Steering Committee and Membership of
the Advisory Council to Improve Outcomes
Nationwide in Heart Failure. Am J Cardiol.
199983(suppl 2A)1A39A.
119
New Approach to the Classification of Heart
Failure
Hunt SA et al. J Am Coll Cardiol.
20013821012113.
120
New Approach to the Treatment of Heart Failure
Hunt SA et al. J Am Coll Cardiol.
20013821012113.
121
CHF OVERVIEW

• Demographics
• Pathophysiology
• Therapy
• Delivery of Care
• Strategic vs. Tactical approaches

122
How do we deliver this care?
123
CHF Tribulations

• How long does it take Physicians to change
  practice behaviors from the time evidence based
  literature emerges?
• 15 days
• 15 weeks
• 15 months
• 15 years
• they never change

124
Examples of the Molasses Effect

• Therapy for MI
• Thrombolysis in Acute MI
• ACE inhibitor use in CHF
• Therapy for Hyperlipidemia

Antman.JAMA.1993 269(2)214
125
Potential Reasons forTreatment Time Lag

• Access to Information
• Insufficient or inconclusive data
• Expert Opinion
• Individual Practitioner Behavior
• System or Hospital resistance
• Financial Constraints
• Patient Biases

126
Medications Perceived Effective for Improving HF
Prognosis by Office-based Physicians
100
90
80
70
60
Physicians ()
50
40
30
20
10
0
ACE inhibitors
Diuretics
Digitalis
Spironolactone
?-blockers
Cleland JGF et al. Lancet. 200236016311639. 13
63 Physicians provided data for 11,062 patients
127
Slow Translation of Clinical Trials Results Into
Routine Clinical Practice
Use of Lipid-Lowering Medications
100
Patients Treated ()
80
4S Study
60
48
42
38
32
40
28
24
18
14
20
10
0
1994
1995
1996
1997
1998
1999
2000
2001
2002
Year
4S StudyScandinavian Simvastatin Survival Study
AMI/ACS patients discharged on lipid-lowering
medications. NRMI 3 and 4, PRISM, PURSUIT, GUSTO
II, TIMI 16, ACCEPT.
128
Percentage of PatientsReceiving ACE Inhibitors
31
27
29
Ejection fraction unknown. The benefits of
improved survival and decreased hospitalization
demonstrated only in symptomatic HF patients with
LVD (EF lt 35). Source CompuRX IMS
129
Utilization of Evidence Based Therapies in Heart
Failure
100
80
69
60
Percent of Patients
40
29
19
20
0
ACE Inhibitors
Beta Blockers
Spironolactone
University Hospital Consortium HF Registry 33
Centers, 1239 patients, Year 2000 Discharge
Medications
130
Hospitalization The Predominant Contributor to
Heart Failure Costs
38.6 Outpatient care 14.7 billion (3.4
visits/year /patient)
60.6 Inpatient care 23.1 billion
0.7 Transplants 270 million
Total 38.1 billion (5.4 of total healthcare
costs)
OConnell JB et al. J Heart Lung Transplant.
199413S107-S112
131
Causes of Hospital Readmission for Congestive
Heart Failure
Diet Noncompliance 24
Rx Noncompliance 24
16 Inappropriate Rx
17 Other
19 Failure to Seek Care
Vinson J Am Geriatr Soc 1990381290-5
132
(No Transcript)
133
Hospital Admissions for Acute CHFRemain on the
Increase Due to

• Inevitable progression of disease
• Rising incidence of chronic heart failure
  (population aging, improved survival with
  AMI/revascularization)
• Incomplete treatment during hospitalization
• Poor application of chronic heart failure
  management guidelines
• Noncompliance with diet and drugs

134
MODELS OF CARECHF

• Community Based
• Home Nursing
• Telemedicine
• Clinic Based
• Primary Care
• Specialty Care
• Hospital Based
• Primary Care
• Specialty Care

Physician
Nurse or Pharmacist
135
CHF Model of Care
Registry
NP/CNS Coordinator
Hospital
Pharmacist Social Worker Dietician Psychiatry Car
e Coordinator
Home Nursing
Primary Care Team MD, NP, RN, /Pharmacist
ER
Cardiology MD mentored NP Transplant Coordinator
Clinic
Multidiscipline
136
Treatment of Decompensated Heart Failure CHF
Disease Management Program


85 Reduction

p0.0001
214 patients 6 months pre-evaluation vs 6 months
post-evaluation
ACEI dose increased (151 mg), diuresed (4
liters), flexible diuretic, home exercise
Ahmanson-UCLA Cardiomyopathy Center
Fonarow JACC199730725-32
137
Impact of Management Programs on the
Hospitalization Rate in Heart Failure
Multidisciplinary
Medical Multidisciplinary
138
Randomized Trials of Disease ManagementPrograms
for Heart Failure
11 Randomized Trials, 2,067 Patients
McAlister Am J Med 2001110378-84
139
Key Elements to Quality Improvement
Why Do Some Hospitals Succeed?

• Access to current and accurate data on treatment
  and outcomes
• Have stated goals
• Administrative support
• Support among clinicians
• Use of pre-printed orders, care maps
• Use of data to provide feedback

Bradley JAMA 20012852604-2611
140
National Registry of Myocardial
InfarctionTherapies at Hospital Discharge in AMI
Patients With and Without CHF in the NRMI
77
HF Absent
HF on Presentation
HF After Presentation
80
60
55
60
48
36
Patients Treated ()
35
40
32
32
30
26
27
26
24
22
20
12
0
Aspirin
Beta-Blocker
ACEInhibitor
Lipid-Lowering
Digoxin
Treatment
Discharge Medications
A total of 606,500 patients with AMI in NRMI 2
and 3 71 did not develop HF,123,938 (20.4)
had HF at presentation, 52,220 (8.6) developed
HF thereafter.Spencer FA et al. Circulation.
20021052605-2610.
141
CHAMPSustained Impact Over an 8-Year Period
NRMI Rx rates (1437 hospitals)
200001
1
96
100
94
Treatment Rate ()
91
92
91
90
89
88
85
78
80
75
72
70
77
68
68
64
65
65
60
52
42
37
40
20
12
6
4
0
Lipid- Lowering Treatment
Aspirin
ACE Inhibitor
Beta-Blocker
Fonarow GC et al. Circulation. 2001104II-711.
142
Impact of In-Hospital Initiation of
Lipid-Lowering Medications on Compliance
12-Month Discontinuation of Therapy Rate
50
41
Plt0.0001
40
30
Percent
20
10
10
0
Outpatient Initiation of Statin After Acute
Statin Initiation Prior to Hospital Discharge
N38832
Coronary Syndrome N22,3791
Canadian cohort study Patients with ACS 66
years or older newly started on statin as
outpatients (cost to patient 2 per
prescription) OPUS-TIMI 16 3883 (38) patients
with ACS (N10,238) started on statin prior to
hospital discharge.1. Jackevicius CA et al.
JAMA. 2002288462-467. 2. Cannon CP. J Am Coll
Cordiol. 200135334A.
143
Initiation Management Predischarge process for
Assessment of Coreg Therapy for Heart Failure
IMPACT-HF Trial
Objective To determine if initiating Carvedilol
therapy prior to hospital discharge in patients
admitted with a primary diagnosis of heart
failure and LVEF ? 40 is safe and effective in
improving the overall use of beta-blockers at 60
days after randomization, as compared to
initiation of any beta-blocker ? 2 weeks
postdischarge at physician discretion.
Presented at AHA Scientific Sessions, GSK
Satellite Symposium, Nov. 18th, 2002, Chicago,
IL. Gattis W, OConnor C, Gheorghiade M. The
Initiation Management of Predischarge Process for
Assessment of Carvedilol Therapy for Heart
Failure (IMPACT-HF) Study Design and
Implications. Rev Cardiovasc Med. 2002, 3(Suppl
3) S48-S54.
144
IMPACT-HF Primary End PointPatients Receiving a
beta-blocker at 60 days
Presented at AHA Scientific Sessions, GSK
Satellite Symposium, Nov. 18th, 2002, Chicago,
IL.
145
Comparative Percentages of HF Patients Receiving
a Beta-Blocker
100
91
75
67
Patient Treatment With Beta-Blockers ()
50
27
25
16
0
IMPACT-HF Carvedilol Predischarge Initiation
Usual Care
Provider/Patient Notification
Nurse Facilitator
Ansari M et al. Circulation. 20031072799-2804 IM
PACT-HF Presented by Gheorghiade M, OConnor C,
and Gattis W, at GSK Satellite Symposium at
Scientific Sessions of the American Heart
Association, November 18, 2002, Chicago, Ill.
146
Outpatient Compliance to Beta-Blocker Therapy
Post-Acute MI
80
Discharged on Beta-Blockers
60
Beta-Blocker Users ()
40
Not discharged on Beta-Blockers
20
0
0
30
90
180
270
365
Days Since Discharge
Butler J et al. J Am Coll Cardiol.
2002401589-1595.
147
In-Hospital Initiation of CardiovascularProtectiv
e Therapies

• Therapy more likely to be initiated by
  physician
• Therapy more likely to be continued by
  physician long-term
• Patients more likely to view therapy as
  essential (heart medication)
• Patients more likely to be compliant (lower
  discontinuation rates)
• Patient more likely to achieve treatment goals
• Early event reduction not missed

Fonarow GC. Circulation. 20011032768-2770.
148
Why a Hospital-Based Systemfor Cardiac
Treatment?

• Patients
• Patient capture point
• Have patients/family attention teachable
  moment
• Predictor of care in community
• Hospital Structure
• Standardized processes/protocols/orders/teams
• JCAHO-ORYX
• Process improvement examples
• CMSQuality Improvement Organizations

JCAHOJoint Commission on the Accreditation of
Healthcare Organizations ORYXLike the JCAHOs
initiative for incorporating outcomes and
measures into accreditation CMSCenters for
Medicare and Medicaid Services.
149
Whats Involved in Starting a Hospital-Based
Treatment Program

• Collect baseline data or use existing data source
• ie, NRMI, CRUSADE registry, or collect data with
  GWTG PMT. Data entry by nurse, case manager,
  PharmD, housestaff, or others
• Select a champion, appoint a team to develop
  treatment algorithms, preprinted orders,
  discharge forms
• Present at lectures and staff in-services
• Present urgent need to improve care
• Review best practice examples
• Lead discussion regarding recommendations on
  protocol improvement
• Collect postintervention data
• Revise protocols and tools to close gaps
• Communicate revisions to key departments
• Repeat cycle frequently (every quarter) CQI

NRMINational Registry of Myocardial Infarction
CRUSADECan Rapid Risk Stratification of Unstable
Angina Patients Suppress Adverse Outcomes
GWTGGet With The Guidelines PMTPatient
Management Tool CQIContinuous Quality
Improvements.
150
Outpatient ManagementTactical Approaches

• Identify patients and develop a registry
• May represent 2-3 of your patient panel
• Chronic Disease Management
• Clinic nurse, NP, PA, pharmacist
• Multidiscipline approach
• Patient Education and Involvement
• Scales and BP cuffs
• Diary

151
Telemedicine
Solution Overview
Health Plan Clinic
Patients Home
LAN Server
Home Hub
Vital Sign Data
Scale
Blood Pressure Unit
Rhythm Strip Recorder
Clinical Intervention as Necessary
152
Outcomes Nurse Outreach Program Plus
Telemedicine
Hospital Readmission Rate/CHF Patient
UMass Memorial Health Center Trial
Source Theo E. Meyer, M.D., D. Phil., UMass
Memorial Health Center, Division
of Cardiology
153
CHF Chronic Disease Management

• Disease management programs reduce
  hospitalizations and costs
• Inconclusive data but a trend towards reducing
  mortality
• Trends towards better QOL
• Successful Models
• Multidisciplinary Team
• Patient Education
• Improved prescribing practices
• Specialized follow-up procedures

McAlister. AM J Med.2001110378-384 A
systematic review of randomized trials of
disease management programs in heart failure.
154
Whats Involved in Starting a Hospital-Based
Treatment Program

• Collect baseline data or use existing data source
• ie, NRMI, CRUSADE registry, or collect data with
  GWTG PMT. Data entry by nurse, case manager,
  PharmD, housestaff, or others
• Select a champion, appoint a team to develop
  treatment algorithms, preprinted orders,
  discharge forms
• Present at lectures and staff in-services
• Present urgent need to improve care
• Review best practice examples
• Lead discussion regarding recommendations on
  protocol improvement
• Collect postintervention data
• Revise protocols and tools to close gaps
• Communicate revisions to key departments
• Repeat cycle frequently (every quarter) CQI

155
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156
(No Transcript)
157
CHF- Easy or Hard
158
Heart Failure in One Minute

• Confirm the clinical diagnosis with an
  echocardiogram
• ?new role for BNP
• Determine the etiology and reverse it, if
  possible (Rx for HTN, stop alcohol, reverse or
  treat ischemia, control HR in AF)

159
Heart Failure in One Minute

• Add Diuretic if neck veins remain elevated (Block
  secondary effects of RAA System)
• Attempt euvolemic status
• Add Aldactone in FTC III-IV pts (RALES)
• ?Eplerenone in post MI (EPHESUS)
• Add ACEI Therapy (Block RAA System)
• May use ARB if ACE intolerant (ELITE II, ValHFT,
  CHARM, VALIANT)
• Add Beta Blockers to lower HR to about 60 beats
  per minute
• Metoprolol, Carvedilol, Bisoprolol

160
Heart Failure in One Minute

• Control BP ( 80 EF)
• May add Hydralazine/Isosorbide (VeHFT Trial)
• Avoid CCB, except for Amlodipine, Felodipine
• May add Digoxin in symptomatic pts, or Afib
• AVOID
• ASA (in non-ischemia DCM) NSAIA
• Coumadin (unless Afib)
• Multidiscipline Approach emphasizing CARE
  MANAGEMENT
• Move away from Episodic Care

161
Therapies of Demonstrated Benefit Across the
Cardiovascular Continuum
Post-MI LV Dysfunction
Mild, Mod, Severe HF
Post-MI
CAD
SOLVD /CONSENSUS (enalapril)
AIRE/SAVE (ramipril/captopril)
ACE Inhibitor
HOPE (ramipril)
HOPE (ramipril)
COPERNICUS (carvedilol, Toprol XL)
CAPRICORN (carvedilol)
BHAT/Norwegian (propranolol/timolol)
TIBBS (bisoprolol)
Beta-Blocker
Aldosterone Antagonist
RALES (spironolactone)
EPHESUS (eplerenone)
HOPEHeart Outcomes Prevention Evaluation
AIREAcuteInfarction Ramipril Efficacy
SAVESurvival and Ventricular Enlargement
SOLVDStudies of Left Ventricular Dysfunction
CONSENSUSCooperative North Scandinavian
Enalapril Survival Study TIBBSTotal Ischemic
Burden Bisoprolol Study BHATBeta-Blocker Heart
Attack Trial CAPRICORNCarvedilol Post-Infarct
Survival Control in Left Ventricular Dysfunction
COPERNICUSCarvedilol Prospective Randomized
Cumulative Survival EPHESUSEplerenone
Post-Acute Myocardial Infarction Heart Failure
Efficacy and Survival Study RALESRandomized
Aldactone Evaluation Study.
162
Heart Failure-Oncology Model
Surgery
Chemotherapy
Remission
Terminal
CHF, LV Fx improves with surgery CABG,
Valve Transplant Mech Heart
CHF, LV Fx improves with medical Rx,
time Diuretics, ACEI,BB Spironolactone Rx
HTN New Therapies Time!
CHF symptoms improve, LV Fx does not Diuretics,
ACEI,BB Spironolactone New Therapies QOL issues
Time!
CHF worsens despite Rx, QOL poor Frank
disc About prognosis Hospice Supportive Care
5-10
20-30
50-60
1
163
CHF SUMMARY Strategic
vs. Tactical
Evidence Based Therapies
ACE-I, B-Blocker
By using
Multidiscipline Education CHF Nurse
Care Management

• Better Compliance with therapies
• Improved Mortality-91 one year survival
• Less than 1 out of 5 patients admitted for heart
  failure per year

164
(No Transcript)