Download Heart Failure - Dartmouth

Congestive Heart Failure:
Strategic vs. Tactical Approaches
while in the Trenches
Alan Kono, MD FACC
Cardiology
Dartmouth-Hitchcock Medical Center
Faculty Disclosure
• I have no financial relationships with vendors
• Even if I do own stock in said vendors, I’ve
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
What do you see?
A Approaching the Bermuda
Triangle
B Hussein’s Oil Fields Burning
C Armageddon
D Not sure, give me more info
Hurricane Isabel September 2003
What are you thinking?
A “Go to Warp Factor 3, Scotty”
-Captain Kirk’s 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
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?
CHF OVERVIEW
•
•
•
•
•
Demographics
Pathophysiology
Therapy
Delivery of Care
Strategic vs. Tactical approaches
Strategic vs. Tactical
• Strategic- of pertaining to…large 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
Webster’s New Collegiate Dictionary
American Heritage Dictionary
CHF OVERVIEW
•
•
•
•
•
Demographics
Pathophysiology
Therapy
Delivery of Care
Strategic vs. Tactical approaches
Heart Failure
A clinical syndrome in which the heart is
unable to pump sufficient blood to meet
the metabolic demands of the body.
Heart Failure
• Approximately 5 million Americans
have CHF (male to female ratio 1:1)
• 550,000 new cases annually
• Incidence of 10/1000 > 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
CHF Patient Population by NYHA Class
Class III
1.20 M
(25%)
Class IV
240 K
(5%)
Class I
1.68 M
(35%)
Class II
1.68 M
(35%)
AHA Heart and Stroke Statistical Update 2001
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
New Approach to the
Classification of Heart Failure
A
B
C
D
Stage
Patient Description
High risk for
developing heart
failure (HF)
Asymptomatic HF
•
•
•
•
•
•
•
•
•
•
•
Symptomatic HF
Refractory
end-stage HF
Hunt SA et al. J Am Coll Cardiol. 2001;38:2101–2113.
Hypertension
CAD
Diabetes mellitus
Family history of cardiomyopathy
Previous MI
LV systolic dysfunction
Asymptomatic valvular disease
Known structural heart disease
Shortness of breath and fatigue
Reduced exercise tolerance
Marked symptoms at rest despite
maximal medical therapy (eg, those
who are recurrently hospitalized or
cannot be safely discharged from the
hospital without specialized
interventions)
Classification of HF: Comparison
Between ACC/AHA HF Stage and
NYHA Functional Class
ACC/AHA HF Stage1
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)
B Structural heart disease but without
symptoms of heart failure
C Structural heart disease with prior or
current symptoms of heart failure
D Refractory heart failure requiring
specialized interventions
NYHA Functional Class2
None
I Asymptomatic
II Symptomatic with moderate exertion
III Symptomatic with minimal exertion
IV Symptomatic at rest
1Hunt
SA et al. J Am Coll Cardiol. 2001;38:2101–2113.
2New
York Heart Association/Little Brown and Company, 1964. Adapted from: Farrell MH et al. JAMA. 2002;287:890–897.
Historical Perspective
• Hemodynamic model
– Preload
– Afterload
– Contractility
• Neurohormonal model
Remodeling model
Risk Factors for Heart Failure
• CAD or history of MI
• Hypertension
• Valvular heart disease
• Alcoholism
• Diabetes
• Congenital heart defects
• Other:
– Obesity
– Age
– Smoking
– High or low hematocrit level
– Obstructive Sleep Apnea
CAD=coronary artery disease; LVH=left ventricular hypertrophy.
CHF OVERVIEW
•
•
•
•
•
Demographics
Pathophysiology
Therapy
Delivery of Care
Strategic vs. Tactical approaches
Hypertension
Viral
Ischemia
Myocardial Injury
Toxins
Valvular
Post
Partum
CAD
HTN
VHD
VIRAL
Pathophysiologic Effects
of Compensatory Mechanisms
in 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
Compensatory Mechanisms:
Frank-Starling Law
Stroke Volume
Maximal
Normal LV
Mild LVD
Normal
Resting
Severe
LVD
Low-Output
Symptoms
Normal Resting
Pulmonary Edema
Congestive Symptoms
Left Ventricular End-Diastolic Pressure
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
Remodeling and progressive
worsening of LV function
Fibrosis, apoptosis,
hypertrophy, cellular/
molecular alterations,
myotoxicity
Morbidity and mortality
Arrhythmias
Pump failure
RAS, renin-angiotensin system; SNS, sympathetic nervous system.
Peripheral vasoconstriction
Hemodynamic alterations
Heart failure symptoms
Fatigue
Activity altered
Chest congestion
Edema
Shortness of breath
SNS Activation Leads Directly to
Impaired Cardiac Function
 CNS sympathetic outflow
 Cardiac sympathetic activity
 Sympathetic activity to
kidneys + blood vessels
121receptors receptors receptors
Myocyte hypertrophy, dilation,
ischemia, arrhythmias, death
Disease progression
Adapted from Packer M. Prog Cardiovasc Dis. 1998;39(suppl I):39–52.
Activation
of RAS
Vasoconstriction
Sodium retention
Remodeling
1 week
3 months
Chamber Enlargement
EDV 137 mL ESV 80 mL
EF 41%
EDV 189 mL ESV 146 mL
EF 23%
Apical 4 Chamber View
Remodeling
Prognosis-Volume
Gaasch, et al CPC 1995
CHF OVERVIEW
•
•
•
•
•
Demographics
Pathophysiology
Therapy
Delivery of Care
Strategic vs. Tactical approaches
The following therapies have been
shown to improve mortality in CHF
•
•
•
•
•
•
Digoxin
ACE inhibitors
Angiotensin Receptor Blockers
Calcium Channel Blockers
B-blockers
Loop Diuretics
CHF THERAPY
ACE-Inhibitors
B-blockers
Pathogenesis and
Therapeutic Approaches
Vasodilators
ACE Inhibitors
 Imepdance
 LV Function
Digoxin
 Cardiac Output
ACE Inhibitor
Salt and Water
Retention
Neurohormone
Activation
{
RAA System
ANF
Catecholamines
Diuretics
Progressive
Heart Failure
B-blockers
Effect of ACE Inhibitors on Mortality
Reduction in Patients With CHF
Mortality
Trial
ACEI
Controls
RR (95% CI)
CONSENSUS I
39%
54%
0.56 (0.34–0.91)
SOLVD (Treatment)
35%
40%
0.82 (0.70–0.97)
SOLVD (Prevention)
15%
16%
0.92 (0.79–1.08)
SAVE
20%
25%
0.81 (0.68–0.97)
AIRE
17%
23%
0.73 (0.60–0.89)
TRACE
35%
42%
0.78 (0.67–0.91)
Chronic CHF
Post MI
SMILE
Average
6.5%
21%
Garg R et al. JAMA. 1995;273:1450–1456.
Data shown from individual trials–not direct comparison data.
8.3%
25%
0.78 (0.52–1.12)
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. 1999;83(suppl 2A):1A–39A.
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.
PATHOPHYSIOLOGIC
ROLE OF ANGIOTENSIN II
Angiotensin II
Vasoconstriction
AT1
Receptor
Aldosterone
Production
Cell Growth
PVR
BP
LVH
Vascular
Remodeling
 Sodium/Water
Retention
 BP
Hypertension. Feb. 1994;23(2):258
ARB
Angiotensin Receptor Blockers
• This-a-sartan and that-a-sartan?
Elite II
Primary All Cause Mortality
1.0
0.8
# of Events
Captopril=250
Losartan = 280
Hazards Ratio(95%) 0.88 (.75,1.05)
p= 0.16
mortality rate = 11%
0
100
200
300
400
Days of Follow Up
500
600
700
Presented at the AHA,
Atlanta 1999 by B.Pitt
M.D.
Effect of Valsartan on Mortality by ACE
Inhibitor/-Blocker Subgroups (Val-HeFT)
n
Not Receiving ACEI
Favors valsartan
Favors placebo
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. 2001;345:1667–1675.
HF NOT AN APPROVED INDICATION
FOR VALSARTAN
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. 2001;38:2101–2113.
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
CHARM
Lancet 362; 759-776 September 2003
VALIANT
• Valsartan, Captopril or Both in MI complicated by
Heart Failure, LV dysfunction or Both
– EF<35% (echo or LV gram)
<40% (MUGA)
• 14,808 pts enrolled
• No significant difference in
– Cardiovascular Death
– Combined Cardiovascular endpoints
• Valsartan showed non-inferiority
Pfeffer. NEJM; 359 (20) 11/03
VALIANT
Pfeffer. NEJM; 359 (20) 11/03
B-Blockers in CHF
Historical 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
B-Blockers in CHF
• Are B-Blockers effective in CHF?
-Yes ( that’s what the experts say)
-No (they didn’t teach that to me in my training)
• Is it a class effect?
-Yes (a B-blocker is a B-blocker)
-No (Designer Drugs are cool)
• Is it safe to use in advanced CHF (FTC IV)?
-Yes, the bookies have the odds
-No, it’s better in less severe patients
• When
should
you
initiate
B-blockers?
-In the ER
-In the Hospital
-In the Clinic
• Are B-blockers safe to use post MI & CHF?
-Yes, I’m feeling lucky
-No, you’re pulling my leg
ß-Blockers: Use in Heart Failure is
Now Supported by Overwhelming
Evidence
• >15,000 patients evaluated in long-term placebocontrolled clinical trials
• Improvement in cardiac function and symptoms;
equivocal effects on exercise tolerance
• Decrease in all-cause mortality by 30%–65%
(P<.0001)
• Decrease in combined risk of death and
hospitalization by 35%–40% (P<.001)
• Effect shown in patients already receiving ACE
inhibitors
Selectivity of -Blocking Agents
MI, HTN, DM, Insulin Resistance
Sympathetic Activation
1
receptors
2
receptors
1 selective
blockade
 non-selective
blockade
1
receptors
 1 ,  2,  1
blockade
Cardiotoxicity
Major Placebo Controlled Trials of
Beta-Blockade in Heart Failure
HF
Severity
Patients
(n)
Follow-up
(yrs)
Target
Dosage
(mg)
Mean Dosage
Achieved
(mg/day)
Effects on
Outcomes
Study
Drug
CIBIS
bisoprolol*
moderate/
severe
641
1.9
5 qd
3.8
All-cause mortality
NS
bisoprolol*
moderate/
severe
2647
1.3
10 qd
7.5
All-cause mortality
34% (P<.0001)
metoprolol
tartrate*
mild/
moderate
383
1
200 qd
108
Death or need for
transplant
(primary endpoint)NS
mild/
moderate
3991
1
200 qd
159
Lancet 1999
metoprolol
succinate#
All-cause mortality
34% (P=.0062)
BEST4
bucindolol*
moderate/
severe
2708
2
50-100
bid
152
All-cause mortality
NS
carvedilol
mild/
moderate
1094
6.5
months
6.25 to 50
bid
45
All-cause mortality†
65% (P=.0001)
carvedilol
severe
2289
10.4
months
25 bid
37
All-cause mortality
 35% (P =.0014)
Circ. 1994
CIBIS-II3
Lancet 1999
MDC
Lancet 1993
MERIT-HF1
NEJM 2001
US Carvedilol2
NEJM 1996
COPERNICUS5
NEJM 2001
†Not
a planned end point.
*NOT AN APPROVED INDICATION; #METOPROLOL SUCCINATE NOT
APPROVED FOR SEVERE HF OR FOR MORTALITY REDUCTION ALONE
Probability of event-free survival

Effect of Carvedilol on Disease
Progression in Mild or Moderate Heart
Failure
1.0
Carvedilol
(n=232)
0.8
Risk reduction
Placebo
48%
(n=134)
P=.008
0.6
0
0
50
100
150
200
Days
250
300
350
400
*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. 1996;94:2800–2806.
Study Results
Total Mortality
Risk reduction: 34%
Percent of patients
2
0
P=0.0062
15
Placebo
n=2001
Metoprolol XL
n=1990
10
5
0
0
3
6 9 12 15 18 21
Months of follow-up
-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
(Bucindolol)*
*HF not an approved indication.
1Packer M. N Engl J Med. 1996;334:1349–1355.
2MERIT-HF Study Group. Lancet. 1999;353:2001–2007.
3CIBIS II Investigators. Lancet. 1999;353:9–13.
4The BEST Investigators. N Engl J Med. 2001;344:1659–1667.
8%
COPERNICUS
All-Cause Mortality
100
% Survival
90
Carvedilol
80
Placebo
70
35%  in risk
60
P=.00013 (unadjusted)
P=.0014 (adjusted)
0
0
3
6
9
12
Months
Packer M et al. N Engl J Med. 2001;344:1651–1658.
15
18
21
COMET*
• More than 3000 patients with class II–IV†
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
*Carvedilol or Metoprolol European Trial
CLASS IV HF NOT APPROVED USE
FOR ANY -BLOCKER
§HF NOT AN APPROVED INDICATION
FOR METOPROLOL TARTRATE
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
Assessments every four months
maximum
during maintenance phase
tolerated
or target dose
(Start: carvedilol 3.125 mg bid, metoprolol tartrate 5 mg bid)
Poole-Wilson PA et al. Eur J Heart Fail 2002;4:321-329.
Primary Endpoint of Mortality
40
Metoprolol
30
20
Carvedilol
Hazard ratio 0.83,
95% CI 0.74-0.93, P = 0.0017
10
0
0
Number at risk
Carvedilol 1511
Metoprolol 1518
1
2
3
4
5
Time (years)
1366
1359
Poole-Wilson PA et al. Lancet 2003;362:7-13.
1259
1234
1155
1105
1002
933
383
352
-Blocker Trials Intervening Within
24 Hours of an Acute Myocardial
Infarction
Study
# of
Patients
Treatment
Groups
Duration
of therapy
Effect on
Mortality
Effect on
Reinfarction
Göteborg1
Study
1,395
Placebo
vs
Metoprolol
3
months
 36%
(P=.03)
NS
MIAMI2
Trial
5,778
Placebo
vs
Metoprolol
15 days
NS
NS
ISIS-13
Trial
16,027
Control
vs
Atenolol
1
week
 15%
(P<.04)
NS
1Hjalmarson A
et al. Lancet. 1981;2(8251):823–827.
Miami Trial Research Group. Am J Cardiol.1985;56(14):15G–22G.
3First International Study of Infarct Survival Collaborative Group. Lancet. 1986;2(8498):57–66.
2The
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. 2000;2:325–332.
CAPRICORN:
All-Cause Mortality
Proportion EvenPt-free
1.00
Carvedilol n=975
0.90
Risk reduction
23%
0.80
Placebo n=984
(2%, 40%)
0.70
P=.031
0.60
0
0
0.5
1
1.5
2
2.5
Years
The CAPRICORN Investigators. Lancet. 2001;357:1385–1390.
Mortality rates: Placebo 15%; Carvedilol 12%
COPERNICUS: Death,
Hospitalization, or Withdrawal
During First 8 Weeks
% Patients With Event
20
15
Placebo n=1133
10
Carvedilol n=1156
5
0
0
2
Weeks
4
6
Weeks
Weeks
Post Randomization
Hazard ratio
(95% confidence
interval):
0.83 (0.68–1.03)
8
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 <25%.
Krum H et al. JAMA. 2003;289:712–718.
At 2 weeks, 97% of patients were either receiving or titrated to 6.25 mg bid
B-Blockers in CHF
• Are B-Blockers Effective in CHF?
-Yes
• Is it a class effect?
-Effficacy seen with Bisoprolol, Metoprolol XL, Carvedilol
• Is it safe to use in advanced CHF (FTC IV)?
-Efficacy and safety established with Carvedilol
• When should you initiate B-blockers?
-May be started in the hospital when euvolemic (IMPACT-HF)
• Are B-blockers safe to use post MI & CHF?
-May be initiated post MI with CHF/LV dysfunction (CAPRICORN)
B-Blockers in CHF
New 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
CHF THERAPY
Calcium Channel Blockers
Digoxin
Diuretics
PRAISE2
1652 patients with CHF of non-ischemic etiology
10 mg amlodipine
50%
45%
40%
35%
30%
25%
20%
15%
10%
5%
0%
HR = 1.09
31.7%
33.7%
placebo
amlodipine
Presented at ACC; Anaheim March 2000
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
(P=NS)
• 28% significant decrease in CHF
hospitalizations compared with placebo
(P<.001)
The Digitalis Investigation Group. N Engl J Med. 1996; 335:490–498.
Digoxin Does NOT Decrease
Mortality... but decreases
hospitalization (6%)
50
Mortality
(%)
40
30
placebo
Digoxin
20
10
0
0
4
8 12 16 20 24 28 32 36 40 44 48 52
Months
Digitalis Investigation Group, N Engl J Med 1997;336:525-33
Randomized Trials of
Loop Diuretics
Randomized Trials of
Aldosterone Blocking Diuretics
• RALES Trial
• EPHESUS Trial
Randomized Aldactone
Evaluation Study (RALES)
1.00
0.95
0.90
Probability of Survival
0.85
0.80
0.75
0.70
Spironolactone*
0.65
0.60
P<.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. 1999;341:709–717.
*NOT INDICATED TO REDUCE
MORTALITY IN HF
EPHESUS: Design
AMI, LVEF 40%, Rales, Standard Therapy
Eplerenone
25–50 mg qd
n = 3100
Randomize 3–14 Days
Post–AMI
1012 Deaths
Placebo
n = 3100
• Total mortality
• CV mortality/CV hospitalization*
Secondary End Points: • CV mortality
• Total mortality/total hospitalizations
Primary End Points:
*CV hospitalization = hospitalization for heart failure, MI, stroke, or ventricular arrhythmia
Relative Risk of Total Mortality
22
20
18
16
14
Placebo
Eplerenone
Cumulative 12
Incidence (%)
10
8
RR = 0.85 (95% CI, 0.75-0.96)
P = 0.008
6
4
2
0
0
3
6
9
12 15 18 21 24 27 30 33 36
Months Since Randomization
Remodeling
Afterload Reduction
Remodeling
Therapy
Remodeling and Survival Effects by
Drug Class
Established Rx Remodeling Effects
ACE-I
ARB
Aldo-B
Beta-B
Survival Effects
Benefit
Benefit
Benefit (+ACEI better) Benefit (+ACEI better)
Benefit
Benefit
Benefit
Benefit
Other Rx
Vasop-I
ET-1-B
TNF-B
Ibopamine
Benefit (ACEI-neutral) Benefit (ACEI-neutral)
No Benefit
No Benefit
No Benefit
No Benefit
Adverse
Adverse
CHF NEW THERAPIES
New Therapies
• Biventricular pacing-LV pacing via the
coronary sinus
• TNF-alpha blockers- for Class III-IV CHF
• Endothelin blockers
• Neutral endopeptidase blockers
• Vasopressin
Biventricular Pacing
Ventricular 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
Overview of Device Therapy
102
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
Cumulative Survival
100%
<90
90%
90-120
80%
120-170
170-220
70%
>220
60%
0
60 120 180 240 300 360
Days in Trial
Adapted from Gottipaty et al.
1
Gottipaty V, Krelis S, et al. ACC 1999 [Abstr];847-4.
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.
Mechanisms
Ventricular Dysynchrony
Click to Start/Stop
Clinical Consequences of
Ventricular Dysynchrony
Abnormal
interventricular
septal wall motion
Grines C, et al. (1989)
Reduced dP/dt
4-Chamber.avi
Xiao H, et al. 1992
Reduced diastolic
filling times
Grines, et al. (1989);
Xiao, et al. (1991)
Prolonged MR
duration
Grines, et al. (1989);
Xiao, et al. (1991)
LV Reverse Remodeling after
CRT
MR area
LV End Systolic and
Diastolic Volumes
Pacing
No pacing
40
No pacing
Pacing
†
*
200
*
175
*
*
150
125
†
*
*
100
Mitral regurgitation (%)
Left ventricular volume (mL)
225
†
35
*†
*
†
30
*
25
*
*
1mo
3mo
20
15
*
*
10
Baseline
1wk
1mo
3mo
N = 25
off-immed off-1wk
off-4wk
Baseline
1wk
off-immed off-1wk
off-4wk
Yu CM, et al, Circulation. 2002;105:438-445.
Cardiac Resynchronization Therapy
Effect on LV Size and Function (MIRACLE)
Paired, Median Changes from Baseline
cm
3
0
-10
-20
-30
3M
6M
p<
0.001
4
3
MR Jet Area
p=
0.008
1
2
-2
0
-3
6M
 Control (n=151)  CRT (n=172)
St. John Sutton M, et al. Circulation. 2003;107:1985-1990.
Doug Smith:
p<
0.001
3M
6M
-1
1
3M
p<
0.001
0
cm
p<
0.001
Absolute %
10
p<
0.001
LVEF
2
LVEDV
Effect of Beta Blocker Therapy
Paired, Median Changes from Baseline at 6 Months
*
*
BB
MR Jet Area
0
4
*
2
-3
BB
No BB
 Control  CRT
* p < 0.05, CRT vs. Control within subgroups
† p < 0.05, CRT vs. CRT between subgroups
St. John Sutton M, et al. Circulation. 2003;107:1985-1990.
Doug Smith:
-1
-2
0
No
BB
1
*
6
2
0.2
LVEF
cm
10
0
-10
-20
-30
-40
8
Absolute %
cm
3
LVEDV
*
*†
BB
No
BB
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
Study design
COMPANION
•Parallel, randomized
• OPT
Randomization
• OPT
• CRT
• OPT
• CRT-D
1
2
+
2
+
Bi-Ventricular Pacing
Criteria for referral
•
•
•
•
NYHA FTC III-IV CHF
EF<30-35%
QRS >130ms (LBBB>RBBB)
Failing “optimal” medical Therapy
• Less data on patients with permanent pacers
• Less data on patients with Afib
CHF OVERVIEW
•
•
•
•
•
Demographics
Pathophysiology
Therapy
Delivery of Care
Strategic vs. Tactical approaches
Approach to the Patient With
Heart Failure
Assessment of LV function
(echocardiogram, radionuclide ventriculogram)
EF 40%
Assessment of fluid volume status
Signs and symptoms of
fluid retention
No signs and symptoms of
fluid 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. 1999;83(suppl 2A):1A–39A.
New Approach to the
Classification of Heart Failure
A
B
C
D
Stage
Patient Description
High risk for
developing heart
failure (HF)
Asymptomatic HF
•
•
•
•
•
•
•
•
•
•
•
Symptomatic HF
Refractory
end-stage HF
Hunt SA et al. J Am Coll Cardiol. 2001;38:2101–2113.
Hypertension
CAD
Diabetes mellitus
Family history of cardiomyopathy
Previous MI
LV systolic dysfunction
Asymptomatic valvular disease
Known structural heart disease
Shortness of breath and fatigue
Reduced exercise tolerance
Marked symptoms at rest despite
maximal medical therapy (eg, those
who are recurrently hospitalized or
cannot be safely discharged from the
hospital without specialized
interventions)
New Approach to the
Treatment of Heart Failure
A
B
C
D
Stage
Treatment
High risk for
developing heart
failure (HF)
Asymptomatic HF
• Diabetes
• Hypertension
• Hyperlipidemia
Symptomatic HF
Refractory
end-stage HF
Hunt SA et al. J Am Coll Cardiol. 2001;38:2101–2113.
• Identify and correct
underlying cause
Modifiy risk factors
• Aggressive Medical Rx
• Slow progression
• Caremanagement
• Advanced Therapies
• Cardiac Transplant
• Device
• Palliative Care
ACE-I ARB
Statins
ACE
?B-blocker
ACE ARB
B-blocker
Aldosterone
CHF OVERVIEW
•
•
•
•
•
Demographics
Pathophysiology
Therapy
Delivery of Care
Strategic vs. Tactical approaches
How do we
deliver this care?
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
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
Potential Reasons for
“Treatment Time Lag”
• Access to Information
• Insufficient or inconclusive
data
• Expert Opinion*
• Individual Practitioner
Behavior
• System or Hospital
resistance
• Financial Constraints
• Patient Biases
Medications Perceived Effective for
Improving HF Prognosis by Officebased Physicians*
100
90
Physicians (%)
80
70
60
50
40
30
20
10
0
Cleland JGF et al. Lancet. 2002;360:1631–1639.
*1363 Physicians provided data for 11,062 patients
Slow Translation of Clinical Trials
Results Into Routine Clinical Practice
Use of Lipid-Lowering Medications
100
80
60
4S Study
40
20
10
14
18
1995
1996
24
28
1997
1998
32
38
42
48
0
1994
1999
2000
2001
Year
4S Study=Scandinavian Simvastatin Survival Study; AMI/ACS patients discharged on lipid-lowering medications.
NRMI 3 and 4, PRISM, PURSUIT, GUSTO II, TIMI 16, ACCEPT.
2002
Utilization of Evidence Based
Therapies in Heart Failure
Percent of Patients
100
80
69
60
40
29
19
20
0
ACE Inhibitors
Beta Blockers
Spironolactone
University Hospital Consortium HF Registry: 33 Centers, 1239 patients,
Year 2000
Discharge Medications
Hospitalization: The Predominant
Contributor to Heart Failure Costs
60.6%
Inpatient care
$23.1 billion
Total = $38.1 billion
(5.4% of total healthcare
costs)
O’Connell JB et al. J Heart Lung Transplant. 1994;13:S107-S112
38.6%
Outpatient care
$14.7 billion
(3.4 visits/year
/patient)
0.7%
Transplants
$270 million
Causes of Hospital Readmission
for Congestive Heart Failure
Diet Noncompliance
24%
16%
Inappropriate Rx
Rx Noncompliance
24%
19%
Failure to Seek
Care
Vinson J Am Geriatr Soc 1990;38:1290-5
17%
Other
Hospital Admissions for Acute CHF
Remain 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
MODELS OF CARE
CHF
• Community Based
Physician
– Home Nursing
– Telemedicine
• Clinic Based
– Primary Care
– Specialty Care
• Hospital Based
Nurse or Pharmacist
– Primary Care
– Specialty Care
Registry
CHF
Model
of
Care
NP/CNS
Coordinator
Hospital
Home Nursing
ER
Pharmacist
Social Worker
Dietician
Psychiatry
Primary Care Team
MD, NP, RN, /Pharmacist
Care Coordinator
Cardiology
MD mentored NP
Transplant Coordinator
Clinic
Multidiscipline
Treatment of Decompensated Heart Failure:
CHF Disease Management Program
85% Reduction
p=0.0001
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 JACC;1997;30:725-32
Impact of Management Programs on
the Hospitalization Rate in Heart
Failure
Multidisciplinary
Medical + Multidisciplinary
Randomized Trials of Disease
Management
Programs for Heart Failure
RR
95% CI
P value
Specialized Care +
M ultidisciplinary Program
0.77
0.69-0.86
<0.01
Telephone Management +
Coordinated Primary Care
1.15
0.96-1.37
NS
11 Randomized Trials, 2,067 Patients
McAlister Am J Med 2001;110:378-84
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 2001;285:2604-2611
CHAMP
Sustained Impact Over an 8-Year Period
UCLA:
100
1992–93
1994–95
1996–97
1998–99
NRMI Rx rates (1437 hospitals):
1
96
92 91 94
91
88 89 90
85
78
80
77
68
68
72
70
75
64
65
60
2000–01
2000–01
52
42
37
40
20
12
6
4
0
Aspirin
Beta-Blocker
Fonarow GC et al. Circulation. 2001;104:II-711.
ACE
Inhibitor
LipidLowering
Treatment
Impact of In-Hospital Initiation of
Lipid-Lowering Medications on
Compliance
12-Month Discontinuation of Therapy Rate
50
41
Percent
40
P<0.0001
30
20
10
10
0
Outpatient Initiation of Statin After Acute
1*
Coronary Syndrome N=22,379
Statin Initiation Prior to
2†
Hospital Discharge N=3883
*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 (N=10,238) started on statin prior to hospital discharge.
1. Jackevicius CA et al. JAMA. 2002;288:462-467.
2. Cannon CP. J Am Coll Cordiol. 2001;35:334A.
IMPACT-HF Trial
Initiation Management Predischarge:
process for Assessment of Coreg
Therapy for Heart Failure
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, O’Connor 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.
IMPACT-HF Primary End Point:
Patients Receiving a beta-blocker at 60
days
Carvedilol Pre-Discharge
Ititiation (N=185)
91%
Physician Discretion
Post-Discharge Initiation
(N=178)
73%
P<.0001
Presented at AHA Scientific Sessions, GSK Satellite Symposium, Nov. 18th, 2002, Chicago, IL.
Patient Treatment With
Beta-Blockers (%)
Comparative Percentages of HF
Patients Receiving a BetaBlocker
100
91
75
67
50
27
25
0
16
Usual
Care
Provider/Patient
Notification
Nurse
Facilitator
IMPACT-HF
Carvedilol
Predischarge
Initiation
Ansari M et al. Circulation. 2003;107:2799-2804
IMPACT-HF Presented by Gheorghiade M, O’Connor C, and Gattis W, at GSK Satellite Symposium at Scientific
Sessions of the American Heart Association, November 18, 2002, Chicago, Ill.
Beta-Blocker Users (%)
Outpatient Compliance to Beta-Blocker
Therapy Post-Acute MI
80
Discharged on Beta-Blockers
60
40
20
Not discharged on Beta-Blockers
0
0
30
90
180
Days Since Discharge
Butler J et al. J Am Coll Cardiol. 2002;40:1589-1595.
270
365
Why a Hospital-Based System
for 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
– CMS—Quality Improvement Organizations
JCAHO=Joint Commission on the Accreditation of Healthcare Organizations; ORYX=Like the JCAHO’s initiative for
incorporating outcomes and measures into accreditation; CMS=Centers for Medicare and Medicaid Services.
Outpatient Management
Tactical 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
Telemedicine
Solution Overview
Patient’s
Home
Health Plan
Clinic
Customer
Intranet
LAN Server
Home
Hub
Vital Sign Data
Scale
Blood Pressure
Unit
Rhythm Strip Recorder
Clinical Review
Software
Clinical
Intervention
as Necessary
Outcomes: Nurse Outreach Program Plus
Telemedicine
Hospital Readmission Rate/CHF Patient
1.7
Prior to trial
Telemedicine
0.13
UMass Memorial Health Center Trial
Source: Theo E. Meyer, M.D., D. Phil., UMass Memorial
Health Center, Division of Cardiology
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.2001:110:378-384 A systematic review of randomized trials of disease
management programs in heart failure.
CHF- Easy or Hard
Therapies of Demonstrated Benefit
Across the Cardiovascular Continuum
CAD
Post-MI
Mild, Mod,
Post-MI LV Dysfunction Severe HF
ACE
Inhibitor
HOPE
(ramipril)
HOPE
(ramipril)
Beta-Blocker
TIBBS
(bisoprolol)
BHAT/Norwegian
(propranolol/timolol)
Aldosterone
Antagonist
AIRE/SAVE
(ramipril/captopril)
CAPRICORN
(carvedilol)
EPHESUS
(eplerenone)
SOLVD /CONSENSUS
(enalapril)
COPERNICUS
(carvedilol, Toprol XL)
RALES
(spironolactone)
HOPE=Heart Outcomes Prevention Evaluation; AIRE=AcuteInfarction Ramipril Efficacy; SAVE=Survival and Ventricular
Enlargement; SOLVD=Studies of Left Ventricular Dysfunction; CONSENSUS=Cooperative North Scandinavian Enalapril
Survival Study; TIBBS=Total Ischemic Burden Bisoprolol Study; BHAT=Beta-Blocker Heart Attack Trial;
CAPRICORN=Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction;
COPERNICUS=Carvedilol Prospective Randomized Cumulative Survival; EPHESUS=Eplerenone Post-Acute Myocardial
Infarction Heart Failure Efficacy and Survival Study; RALES=Randomized Aldactone Evaluation Study.
Heart Failure-Oncology Model
Surgery
Chemotherapy
CHF, LV Fx
CHF, LV Fx
improves
improves with
with surgery medical Rx, time
CABG, Valve
Transplant
Mech Heart
5-10%
Remission
Terminal
CHF symptoms CHF worsens
improve, LV Fx despite Rx,
does not
QOL poor
Diuretics, ACEI,BB
Spironolactone
Rx HTN
New Therapies
Time!
Diuretics, ACEI,BB
Spironolactone
New Therapies
QOL issues
Time!
20-30%
50-60%
Frank disc
About prognosis
Hospice
Supportive Care
1%
CHF SUMMARY
Strategic vs. Tactical
Evidence Based Therapies
ACE-I, B-Blocker
Care Management
Multidiscipline
Education
CHF Nurse
By using
• Better Compliance with therapies
• Improved Mortality-91% one year survival
• Less than 1 out of 5 patients admitted for
heart failure per year