Evidence Based Treatment for Heart Failure

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Promising Therapiesfor Heart Failure
Gregg C. Fonarow, MD
Eliot Corday Professor of Cardiovascular Medicine
and Science UCLA Division of Cardiology Director,
Ahmanson-UCLA Cardiomyopathy Center Director,
UCLA Cardiology Fellowship Training
Program Co-Director, UCLA Preventative Cardiology
Program Los Angeles, California
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Background on Heart Failure

• One of the few major cardiovascular diseases
  risingin incidence
• Over 1 million patients hospitalized this year
  12 million outpatient office visits
• HF hospitalizations one of largest expenses for
  CMS1,2
• Mortality rates remain very high

1American Heart Association. 2004 Heart and
Stroke Statistical Update. Dallas, Texas
American Heart Association 2002. 2Hunt SA et
al. ACC/AHA guidelines for the evaluation and
management of chronic heart failure in the adult.
2001.
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Therapies Demonstrated to ReduceMortality in
Heart Failure

• ACE Inhibitors
• Beta Blockers
• Aldosterone Antagonists
• ICD
• LVEF lt 35, Class II or III
• Cardiac Resynchronization ICD
• LVEF lt35, QRS gt120 ms, Class III or IV

• The CONSENSUS Trial Study Group. N Engl J Med.
  19873161429-1435.
• Packer M et al. N Engl J Med. 19963341349-1355.
• Pitt B et al. N Engl J Med. 1999341709-717.
• Moss A et al. N Engl J Med. 19963351933-1940.
• Abraham WT et al. N Engl J Med.
  20023461845-1853.

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New Therapies for Heart Failure

• Natriuretic peptides
• Endothelin antagonists
• Vasopeptidase inhibitors
• Cytokine antagonists
• Statins
• Erythropoeitin

• External enhancedcounter pulsation
• Cardiac resynchronization therapy
• Routine use of implantable cardiac defibrillators
• Ventricular constraint devices
• Cell transplantation
• Total artificial heart / permanent LVADs

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Heart Failure Pathophysiology
Fall in LV performance
Myocardial injury
Activation of RAAS, SNS, ET, and others
ANP BNP
Peripheral vasoconstriction Hemodynamic
alterations
Myocardial toxicity
Remodeling and progressive worsening of LV
function
Heart failure symptoms
Morbidity and mortality
Fonarow GC. Rev Cardiovasc Med. 200127-12.
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Beneficial Effects ofB-Type Natriuretic Peptide
Fibroblast
Cardiac Myocyte
Peripheral Artery
Coronary Artery
Hypertrophy Decreased wall stress Decreased O2
consumption Improved relaxation
Hyperplasia Collagen synthesis Anti-fibrotic
Vasodilation Endothelial function Hypertrophy Impr
oved compliance
Vasodilation Endothelial function
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The Effects of Nesiritide on Neurohormones
Plt0.001
860
900
P0.06
800
690
Plt0.05
670
700
595
600
496
500
Before nesiritide
383
During nesiritide
400
300
200
100
0
Norepinephrine(pg/mL)1
Aldosterone(pmol/L)1
Endothelin-1(pg/dL)2

• Abraham WT et al. J Card Fail. 1998437-44.
• Aronson D et al. J Am Coll Cardiol. 200137(2
  suppl A)148A.

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Cardiac Fibrosis in Mice Lacking BNP
Tamura et al. Proc Natl Acad Sci.
2000974239-4244.
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ANP Inhibits LV Remodelingin Patients With Acute
MI
P0.034(ANOVA)
P0.034(ANOVA)
P0.009(ANOVA)
60
120
60


50
55
100


LVEDVI (mL/m2)
LVESVI (mL/m2)
LVEF ()
40
50
80
30
45
60
20
40
1 Month
1 Month
Baseline
1 Month
Baseline
Baseline
ANP
Nitroglycerin
Plt0.001Plt0.01Plt0.05
Hayashi M et al. J Am Coll Cardiol.
2001371820-1826.
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Potential Use of Nesiritide in the Outpatient
Management of Advanced HF

• Absence of inotropic activity
• Favorable hemodynamic profile
• cGMP-mediated inhibition of vasoconstriction1
• targets CG-A-receptorrich vascular beds in the
  heart and kidney
• Neurohormonal antagonist2
• Reduces aldosterone
• Inhibits norepinephrine
• Antifibrotic3
• Inhibits cardiac fibroblast proliferation
• Modulates ventricular remodeling in animal models
• Improves cardiac wall elasticity

1. Chen HH, Burnett JC. Curr Cardiol Rep.
20002198-205.2. Abraham WT et al. J Card Fail.
1998437-44.3. Tamura N et al. Proc Natl Acad
Sci USA. 2000974239-4244.
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FUSION Trial Study Design
n70

• Group A Usual long-term cardiac medications
  (excluding nesiritide)may include inotropic
  therapy

• Group B Usual long-term cardiac medications
  (excluding inotropes) plus serial infusions of
  nesiritide
• Initial dose (week 1) 0.5 µg/kg bolus plus
  0.0025 µg/kg/min infusion
• Weeks 2 to 12 adjustable from half to double
  the initial dose, 1 to 3 times per week

N210
n70

• Group C Usual long-term cardiac
  medications(excluding inotropes) plus serial
  infusions of nesiritide
• Initial dose (Week 1) 1.0 mg/kg bolus plus 0.005
  mg/kg/min infusion
• Weeks 2 to 12 adjustable from half to double
  the initial dose, 1 to 3 times per week

n70
At the investigators discretion. Silver MA et
al. J Card Fail. 20028(4 suppl 1)187.
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FUSION Improvement in Left Ventricular Systolic
Function
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FUSION Results Summary

• Nesiritide was safely administered in an
  outpatient setting for 12 weeks most patients
  received highest dose allowed
• Symptomatic hypotension occurred more frequently
  in the Standard Care group
• Subjects on nesiritide were alive and out of
  hospital longer compared to Standard Care.
  Consistent with previous trials, higher risk
  patients may derive more benefit
• No mortality concern compared to Standard
  Care.Fewer deaths in nesiritide group
• Significant improvement in Clinical Status
  assessed by Physician
• FUSION pilot supports further development for
  aPhase III study

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Chronically Implanted Hemodynamic Monitor
Chronicle Device
RVSP RVDP, estimated PAD dP/dt and dP/dt
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Implantable Hemodynamic Monitor
UCLA Cardiac Arrhythmia Center
Ahmanson UCLA Cardiomyopathy Center
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Chronically Implanted Hemodynamic Monitor
68y/o male DM, severe diffuse IHD, EF 45, severe
diastolic dysfunction, chronic renal
insufficiency Chronic Meds torsemide 150
bid metolazone prn spironolactone 50
bid atenolol 25 qDay Non-compliant, admit with
class IV CHF, 4 lb weight gain
Heart Rate
RV Systolic Pressure (mmHg)
RV Diastolic Pressure (mmHg)
--- mean pressures during/after nesiritide
--- mean pressures before nesiritide
ePAD (estimated pulmonary arterial diastolic)
Pressure (mmHg)
Nesiritide IV diuretics
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Cytokines and Pathophysiologyof Heart Failure

• TNF-alpha levels are elevated in patients with
  heart failure
• Administration of TNF decreases contractility
  (myocardial depressant factor of sepsis)
• TNF is an independent risk factor for mortality
• Animal models that over-express TNF develop
  cardiomyopathy and HF
• TNF-blocking therapy is beneficial in
  inflammatory diseases, such as rheumatoid
  arthritis

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Risk ratios for death or CHF hospitalization
Anti-TNF Therapy forHeart Failure
RECOVER randomized 900 patients to placebo or
etanercept once per week or 2 times per week.
RENAISSANCE randomized 900 patients to placebo or
etanercept 2 times per week or 3 times a week.
Mann et al. Presented at The European Society of
Cardiology's Heart Failure Update 2002.
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Heart Failure Pathophysiology
Fall in LV performance
Myocardial injury
Activation of RAAS, SNS, ET, and others
ANP BNP
Peripheral vasoconstriction Hemodynamic
alterations
Myocardial toxicity
Remodeling and progressive worsening of LV
function
Heart failure symptoms
Morbidity and mortality
Fonarow GC. Rev Cardiovasc Med. 200127-12.
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Endothelin Antagonist Bosentan forLowering
Cardiac Events (ENABLE) Trial
Presented at American College of Cardiology 51st
Annual Scientific Session.
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Anemia and Heart Failure

• Anemia is common in patients with heart failure
• Little was known regarding the relationship of
  anemia to heart failure symptoms and exercise
  capacity in HF
• Little was known regarding the relationship of
  anemia to mortality in HF

Horwich and Fonarow. J Am Coll Cardiol.
2002391780-1786.
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Relationship Between Anemiaand Heart Failure
Precipitating Cause
Anemia
Heart Failure
Precipitating Cause Role in Progression?
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Impact of Anemia in AdvancedHeart Failure Study
Design

• Analyzed a cohort of 1061 patients with advanced
  heart failure (NYHA Class III or IV and LVEF
  lt40)
• Mean LVEF 22, Peak VO2 13.1, SBP 109, DBP 67,HR
  90, PCW 25, CI 2.1 and 1 year death UT of 35
• Patients were divided into hemoglobin (Hb)
  quartilesQ1 lt12.3 Q2 12.3-13.6 Q3 13.7-14.8
  Q4 gt14.9 g/dL
• Mean Hgb was 13.6 g/dL (range 7.1-19.0)

Horwich and Fonarow. J Am Coll Cardiol.
2002391780-1786.
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Impact of Anemia on Heart Failure Symptoms and
Functional Status

• Hemoglobin quartiles
• Parameter Q1 Q2 Q3 Q4 ANOVA
• LVEF 23.0 22.2 22.2 22.0 NS
• NYHA 3.74 3.67 3.54 3.57 P0.0001
• Peak VO2 12.9 12.4 13.8 14.6 P0.0001

Horwich and Fonarow. J Am Coll Cardiol.
2002391780-1786.
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Relationship Between Hemoglobinand Mortality in
Patientswith Advanced Heart Failure
1
0.8
Hbgt14.8
Survival ()
Hb 13.7-14.8
Hb 12.3-13.7
0.6
P0.00001
Hblt12.3
0.4
0
2
4
6
8
10
12
Months
Horwich and Fonarow. J Am Coll Cardiol.
2002391780-1786.
30
Impact of Anemia on Mortalityin Heart Failure
Horwich and Fonarow. J Am Coll Cardiol.
2002391780-1786.
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Anemia and Heart Failure

• Anemia is common in patients with heart failure,
  especially those with advanced disease
• Anemia is independently associated with increased
  HF symptoms and worse exercise capacity
• Anemia is independently associated with increased
  mortality
• Pilot studies have shown erythropoietin improves
  functional capacity and reduces symptoms

Horwich and Fonarow. J Am Coll Cardiol.
2002391780-1786.
32
Study of Anemia in Heart Failure Trial
(STAMINA-HF)

• Randomized, double-blind trial of darbepoetin
  alfa on exercise capacity in heart failure
• Class II-IV HF, due to systolic dysfunction
  (LVEF lt0.40)
• Anemia (Hb 9.0 to 12. 5 mg/dL)
• Darbepoetin vs placebo
• Exercise testing, QOL, global score, mortality
• Ongoing clinical trial

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Statins and Heart Failure

• Statins are of proven benefit in coronary heart
  disease, reducing the risk of atherosclerotic
  events and new onset heart failure
• Approximately 2/3 of HF patients in US have CHD
• Non-lipid effects of statins may be beneficial in
  HF regardless of etiology
• Low total cholesterol and lipoprotein levels
  associated with increased mortality in HF
  patients
• No prospective trials of statins in HF

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Effect of Pravastatin on PatientsWith and
Without LV Dysfunction
Placebo
Pravastatin
50
RR 2.1
40
RR 1.5
32
30
25
24
CHD Event Rate ()
20
20
10
0
LVEF 0.40
LVEF gt0.40
CARE (706 patients with LVEF between 0.25 and
0.40) Sacks. N Engl J Med. 19963351001-1009.
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Relationship Between Total Cholesterol and
Mortality in Advanced Heart Failure
100
90
P0.00001
P0.00001
80
P0.00001
70
Quintile 1
60
Quintile 2
Quintile 3
50
Death or Urgent Tx ()
Quintile 4
40
Quintile 5
30
20
10
0
Total cohort
Ischemic
Non-ischemic
(n1134)
CMY (n542)
CMY (n592)
1134 Advanced HF patients Q1 lt129 Q2 129-160
Q3 161-189 Q4 190-224 Q5 gt224 Horwich. J Card
Failure. 20028216-224
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Potential Non-Ischemic Mediated Benefits of
Statins in Heart Failure

• Effects on myocardial cellular function
• Effects on endothelial function
• Down-regulation of angiotensin AT-1 receptor
• Restoration of autonomic function
• Neoangiogenesis
• Inhibition of pro-inflammatory cytokines

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Amelioration of Angiotensin IIInducedCardiac
Injury by a Statin
Rats transgenic for human renin and
angiotensinogen, Rx with cerivastatin vs control
vs SD rats. Dechend. Circulation. 2001104576.
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Statins Down-Regulate Angiotensin II (AT-1)
Receptors in Humans
AT-1 receptor density
10
8
6
Bmax fmol/mg protein
Plt0.01
4
1.8
2
0
Baseline
Statin(6 weeks)
AT-1 receptor expression pre- and
post-simvastatin or atorvastatin 20-40
mg. Nickenig. Circulation. 19991002131.
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Statins Attenuates LV Remodeling and Heart
Failure after Experimental MI
Coronary ligation fluvastatin attenuated
remodeling, LVEDP, cell hypertrophy, decreased
myocardial MMP,increased eNOS expression Hayashid
ani. Circulation. 2002105868.
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Statins Potential LDL-Dependent and
LDL-Independent Effects
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Association Between Statin Use and Mortalityin
Patients with Advanced Heart Failure
Ischemic HF
Non-ischemic HF
100
100
Statin Rx
Statin Rx
80
80
60
60
Surviva ()
Survival ()
No Statin Rx
40
40
No Statin Rx
Plt0.001
20
Plt0.001
20
0
0
0
3
6
9
12
15
18
21
0
3
6
9
12
15
18
21
Months
Months
551 Advanced HF patients (51 on statins 79 of
CAD, and 29 non-CAD) Horwich, Fonarow. J Amer
Col Cardiol. 200443642-648.
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Association Between Statin Use and Mortalityin
Patients with Advanced Heart Failure
Harzard ratios and 95 CI for endpoints
Death or Urgent Transplant HR 0.44 (95 CI
0.30-0.67) P0.0001 Death From Any Cause HR 0.52
(95 CI 0.30-0.90) P0.017 Progressive Heart
Failure Death HR 0.46 (95 CI 0.20-1.05)
P0.055 Sudden Death HR 0.47 (95 CI 0.16-1.37)
P0.152
1.0
0.5
0.1
1.5
2.0
No Statin Better
Statin Better
Horwich, Fonarow. J Amer Col Cardiol.
200443642-648.
43
Association Between Statin Use and Mortalityin
Patients with Advanced Heart Failure
100
90
No Statin Rx
Statin Rx
80
70
60
HR0.44
P0.002
Death or Urgent Transplant ()
50
HR0.49
HR0.44
HR0.22
40
P0.002
Plt0.0001
P0.01
HR0.38
30
P0.05
20
10
0
Men
Women
TC 163
TC gt 163
No
mg/dL
mg/dL
Transplant
Horwich, Fonarow. J Amer Col Cardiol.
200443642-648.
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Association Between Statin Use and Mortality in
5195 Patients with Heart Failure
10
Ischemic HF
Non-Ischemic HF
0
-10
-20
Mortality Risk
-30
-40
-42.0
-50
-46.0
(P0.038)
(P0.002)
-60
-70
5195 HF patients in ELITE II and 5 HF Centers
Statin use in only 20 of patients Anker. HFSA.
2002.
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Use of Lipid-Lowering Medicationsin Recent Heart
Failure Trials
100
80
60
45
41
40
26
23
11
20
0
MERIT HF
BEST
ELITE II
CHARM
ENABLE
Krum. J Am Coll Cardiol. 2002391567-1573.
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Statins and Heart Failure

• Ongoing placebo-controlled clinical trials are
  testing statins as therapy for HF
• Observational studies show that statin use is
  associated with lower mortality in ischemic HF
  and non-ischemic HF
• Until statins are proven not to benefit HF
  patients,all HF pts with atherosclerosis,
  diabetes, or CHDrisk equivalents should be
  treated with statins

Horwich, Fonarow. J Amer Col Cardiol.
200443642-648.
47
Sleep Disordered Breathingand Heart Failure

• High incidence of sleep-disordered breathingin
  patients with heart failure (50)risk factors
  male, age, atrial fib
• Associated with increased arrhythmias, worsened
  ventricular function, and higher mortality
• Randomized trials have demonstrated
  nightlyapplication of continuous positive airway
  pressure (CPAP) increases LVEF, reduces MR,and
  improves QOL
• Ongoing randomized trials of CPAP (CANPAP)
• Recently CRT shown to reduce CSA episodes
• Recommend screening patients with
  HF(in-laboratory polysomnography)

Bradley. Circulation. 20031071822.
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Cardiovascular Effects of Continuous Positive
Airway Pressure (CPAP) in Patients with HF and
Obstructive Sleep Apnea
LVEF 25.0 to 33.8 (Plt0.001)
LVEDD 54.5 to 51.7 mm (P0.009)
24 HF patients with OSA randomized to CPAP vs
control. Kaneko. N Engl J Med. 20033481233-1241.
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Cell Transplantation
x100
Skeletal Myoblasts, Bone Marrow Derived Stem
Cells, Peripheral Stem Cells
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Autologous Bone Marrow Cells to Improve
Ventricular Function in Post Myocardial
Infarction Patients After PCI BOOST
Randomized, controlled trials to investigate the
percutaneous delivery of autologous bone-marrow
cells (BMCs) to infarct-related coronary arteries
P0.0026 BMC vs control
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Percutaneous Transvenous Cellular
Cardiomyoplasty A Novel Nonsurgical Approachfor
Myocardial Cell Tx
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Device Therapy for Heart Failure

• Cardiac resynchronization therapy (CRT)
• Implantable cardioverter-defibrillators (ICD)
• Ventricular assist devices
• Bridge to transplant
• Destination therapy
• Totally implanted artificial hearts
• Cardiac reshaping devices

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Mechanical Ventricular Constraintas a Therapy
for Heart Failure
Acorn CorCap Cardiac Support Device
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Mean Body Weight Changes During Hospitalization
Vasopressin Antagonist for Heart FailureACTIV
in CHF Trial
24 Hours
Discharge
0
-1
-2


Kg

-3
-4


-5
Placebo
Tolvaptan 30 mg
Tolvaptan 60 mg
Tolvaptan 90 mg
Plt0.05 vs Placebo
Gheorghiade M. JAMA. 20042911963-1971.
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60-Day All-cause Mortality
Vasopressin Antagonist for Heart FailureACTIV
in CHF Trial
Plt0.05
P lt0.05
20
18.7
20
17.8
Placebo
Tolvaptan
13.2
9.1
8.7
Percent ()
10
5.5
5.4
0
N 80 239 16 53 30 110 41 163 (
20) (22) (37) (46) (51) (68)
Overall
Hyponatremia
BUN
Congestion
(Na lt136 mEq/L)
(gt 29 mg/dL)
Edema, Dyspnea, and JVD at baseline
Gheorghiade M. JAMA. 20042911963-1971.
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Ultrafiltration for Acute Heart Failure

• Removal of excess volume mechanically
• A simplified peripheral ultrafiltration system
  including a miniaturized disposable circuit
  developed for patients with volume-overload
  states
• Evaluated in observational studies further
  trials underway
• Series of 25 AHF pts with 5 lb net weight loss,
  improved NYHA status, reduction in BNP levels,
  and stable renal function

Jaske B. J Card Fail. 20039227-231.
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Ultrafiltration for Decompensated Heart
FailurePre- Versus Post- Ultrafiltration Weight
-2.6 kg
Effect of Ultrafiltration on Signs and Symptoms
of HF
Plt0.0001
140
130
Baseline
Post 24hr
120
Orthopnea
-36
21
12
-32
110
PND
13
5
Weight (kg)
-44
JVD
23
12
100
-20
Rales
15
10
91.9
89.3
90
-24
S3
8
2
-24
Peripheral Edema
24
18
80
70
60
Pre-treatment
Post-treatment
Jaske B. J Card Fail. 20039227-231.
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Promising Therapies for Heart Failure

• There are a significant number of promising
  therapies for heart failure
• In the past few years, prophylactic ICD and CRT
  have moved from promising therapies to standards
  of HF care
• As there is no perfect surrogate marker in heart
  failure, to move from promising therapy to
  standard of care requires large-scale mortality
  trials
• As such, we can be reasonably assured that there
  will be significant opportunities for clinical
  investigators in heart failure for the
  foreseeable future

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Heart Failure RagesThrough American Cities