HFU Special Populations

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Heart Failure Therapy in Special Populations
The Same or Different?
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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Heart Failure Therapy in Special Populations
Similar or Different

• Who are the special populations?
• Elderly
• Women
• African Americans
• Specific races/ethnicities
• Diabetic patients

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Demographic Projections
2010 US Population by Race
2020 US Population by Race
Asian/PacificIslander
Asian/PacificIslander
American Indian
American Indian
Hispanic
Hispanic
63
67
AfricanAmerican
AfricanAmerican
Non-Hispanic White
Non-HispanicWhite
In 2000 Non-Hispanic Whites 71.4 By 2050
Non-Hispanic Whites 53
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ADHERE RegistryExecutive Summary
All Enrolled Discharges in the Last 12 Months
(July 1, 2002 June 30, 2003)
Indented percentages are calculated based on the
number of patients presented in the preceding
row, rather than the number of patients for the
column. The ADHERE Registry database. Second
Quarter 2003 National Benchmark Report.
Sunnyvale, CA Scios Inc. November, 2003.
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Clinical Characteristics and Outcomes in Patients
Admitted with Heart Failure with Preserved
Systolic FunctionA Report from the ADHERETM
Database Demographics
LVEF lt40
LVEF gt40
Plt.0001.
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Heart Failure in Women Overview

• Affects older women disproportionately
• Risk factors include hypertension, diabetes,
  obesity
• More likely to have heart failure with preserved
  systolic function
• Better prognosis than in men
• Under-represented in clinical trials
• Perhaps lesser responsiveness to ACE inhibitors
  similar responsiveness to b-blockers

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Long-Term Trends in Mortality with Heart Failure
Temporal Trends in Age-Adjusted Mortality After
the Onset of Heart Failure
5-Year Mortality, (95 CI)
1-Year Mortality, (95 CI)
30-Day Mortality, (95 CI)
Women
Men
Women
Men
Women
Men
Period
57 (43-67)
70 (57-79)
28 (16-39)
30 (18-40)
18 (7-27)
12 (4-19)
19501969
59 (45-69)
75 (65-83)
28 (17-38)
41 (29-51)
16 (6-24)
15 (7-23)
19701979
51 (39-60)
65 (54-73)
27 (17-35)
33 (23-42)
10 (4-16)
12 (5-18)
19801989
45 (33-55)
59 (47-68)
24 (14-33)
28 (18-36)
10 (3-15)
11 (4-17)
19901999
All values were adjusted for age (lt55, 55-64,
65-74, 75-84, and 85 years). Levy D et al. N
Engl J Med. 20023471397-1402.
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OutcomesWomen and ACE Inhibitorsfor Heart
Failure
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Combined Treatment and Prevention Study Outcomes
with ACE Inhibitors in Heart Failure
Female
Male
CONSENSUS
CONSENSUS
SAVE
SAVE
SOLVD (Prev)
SOLVD (Prev)
SOLVD (Tx)
SOLVD (Tx)
SMILE
SMILE
TRACE
TRACE
Combined
Combined
0.4
0.82
1.1
1.9
0.4
0.92
1
1.9
Relative Risk
Relative Risk
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Prevention Study Outcomes with ACE Inhibitors in
Heart Failure
Prevention Studies
Female
Male
SAVE
SAVE
SOLVD (Prev)
SOLVD (Prev)
SMILE
SMILE
Combined
Combined
.45
0.96
1.9
1
.4
0.4
0.83
1.1
1.9
1
Relative Risk
Relative Risk
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Treatment Study Outcomes withACE Inhibitors in
Heart Failure
Treatment Studies
Female
Male
CONSENSUS
CONSENSUS
SOLVD (Tx)
SOLVD (Tx)
TRACE
TRACE
Combined
Combined
.45
0.8
1.9
1
.45
0.9
1.9
1
.4
Relative Risk
Relative Risk
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OutcomesWomen and b-Blockers in Heart Failure
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b-Blockers in Heart FailureOutcomes
No. of DeathsPlacebo/b-blockade
No. RandomizedPlacebo/b-blockade
Favorsb-blockade
FavorsPlacebo
CIBIS II
FemalesMalesAll
35/18193/138228/156
258/2571062/10701320/1327
MERIT-HF
33/31184/114217/145
447/4511554/15392001/1990
FemalesMalesAll
COPERNICUS
NPNP190/130
NPNP1133/1156
FemalesMalesAll
All 3 Studies
FemalesMalesAll
1.0
1.8
0.0
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Heart Failure Therapy in Special Populations
Similar or Different

• How should the elderly and women with HF be
  treated?
• There are no compelling data to suggest that the
  elderly or women do not realize important
  survival benefits from the combination of ACE
  inhibitors and b-blockers, but subtle differences
  in the response to medical therapy may be
  present additional investigation may be
  warranted the elderly may actually have a
  greater response to medical therapy for HF

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Heart Failure in African Americans Overview

• Affects 3 of the African American population
• Atypical natural history
• Unique epidemiology
• Lower incidence of associated epicardial coronary
  artery disease
• More likely to be associated with a historyof
  hypertension
• Worrisome prognosis
• Higher rate of hospitalization
• Likely to have similar mortality risk
• Question of altered responses to medical therapy

Yancy CW. J Card Fail. 20006183-186.
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Heart Failure inAfrican Americans Etiology

• Unique natural history
• Occurs at an earlier age
• Associated with more advanced left ventricular
  dysfunction at time of diagnosis
• Worse clinical class at time of diagnosis
• Higher incidence of left ventricular hypertrophy,
  especially concentric hypertrophy
• Lack of definitive relationship between
  psychosocial factors and onset of disease

Yancy CW. J Card Fail. 20006183-186.
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Heart Failure inAfrican Americans Etiology
Patients With Coronary-Artery-DiseaseBased HF
80
60
40
Percent
20
0
V-HeFT I
V-HeFT II
SOLVD
US Carv
BEST
MERIT-HF
Patients With Hypertension-Based HF
80
60
Percent
40
20
0
V-HeFT I
V-HeFT II
SOLVD
US Carv
BEST
MERIT-HF
AA
non-AA
The BEST Investigators. N Engl J Med.
20013441659-1657 Packer M et al. N Engl J Med.
19963341349-1355 MERIT-HF Study Group. Lancet.
19993532001-2007 Cohn JN et al. N Engl J Med.
19863141547-1552Cohn JN et al. N Engl J Med.
1991325303-310 The SOLVD Investigators. N Engl
J Med. 1991325293-302.
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Heart Failure inAfrican Americans

• The emerging influence of genetic polymorphisms
  ie, heart failure in African Americans

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Candidate Genetic Polymorphisms That May
Participatein the Pathogenesis of
Hypertensionin African Americans

• Transforming growth factor-b1
• Endothelin-1
• b1-receptor polymorphisms
• Aldosterone synthase
• Nitric oxide synthase
• 825 T-allele G-protein subunit

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Potential Mechanisms ofHeart Failure in African
Americans

• ?1-adrenergic receptor polymorphism
• Described polymorphism at amino acid position 389
  (Gly 0.26 or Arg 0.74)
• Isoproterenol-stimulated adenyl cyclase activity
  markedly higher with Arg-389
• Increased coupling with Gs with Arg-389
• Gly-389 associated with decreased adenyl cyclase
  activity and decreased Gs coupling
• These findings could be operative in the
  pathophysiology of HF or response to ?-blockers

Mason DA et al. J Biol Chem. 199927412670-12674.
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OutcomesAfrican Americansand ACE Inhibitors
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Ethnic Reanalysis of SOLVD Trial
Exner DV et al. N Eng J Med. 20013441351-1357.
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CHF Mortality in White Patients V-HeFT II
0.8
Enalapril (E)HYDISO (HI)
0.7
0.6
0.5
Cumulative Mortality
0.4
0.3
0.2
0.1
E vs HI Plt.02
0.0
0
6
12
18
24
30
36
42
48
54
60
66
Months
HYD-ISO, hydalazyne plus isosorbide
dinitrate. Carson P et al. J Card Fail.
19995178187.
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CHF Mortality in African American Patients
V-HeFT II
0.8
Enalapril (E)HYDISO (HI)
0.7
0.6
0.5
Cumulative Mortality
0.4
0.3
0.2
0.1
E vs HI Plt.95
0.0
0
6
12
18
24
30
36
42
48
54
60
66
Months
Carson P et al. J Card Fail. 19995178187.
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OutcomesAfrican Americansand b-Blockers
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Outcomes with b-Blockersin Heart Failure
White/nonblack
BEST
COPERNICUS
MERIT-HF
US Carvedilol HF
Combined
.2
.69
2
1
Relative Risk
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Outcomes with b-Blockers in Heart Failure
Black
BEST
COPERNICUS
MERIT-HF
US Carvedilol HF
Combined
.2
.97
2
1
Relative Risk
30
BEST All-Cause Mortality by Race
1.0
1.0
17
18
0.8
0.8
Bucindolol
Placebo
Probability of Survival
Placebo
Bucindolol
0.6
0.6
P.01 Total Events 652
P.27 Total Events 208
0.4
0.4
0
6
12
18
24
30
36
42
0
6
12
18
24
30
36
42
Months Post-randomization
Months Post-randomization
Nonblacks (n2081)
Blacks (n627)
The b-Blocker Evaluation of Survival Trial
Investigators. N Engl J Med. 200134416591667.
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Effect of Carvedilol in Black Patients with Heart
Failure
All-cause mortality all-cause hospitalization
COPERNICUS1 (n121)
US Carvedilol Trials2 (n217)
All-cause mortality cardiovascular
hospitalization
All-cause mortality heart failure
hospitalization
All-cause mortality
0
0.4
0.8
1.2
1.6
2
Favors carvedilol
Favors placebo
1. Packer M. Presented at AHA 2000 (mean
duration 10.5 months).2. Yancy CW. N Engl J Med.
200134413581365. (mean duration 6.5 months).
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COPERNICUS Effect of Race on Outcomes
All-cause mortality all-cause hospitalization
Blacks (n121)
Nonblacks (n2168)
All-cause mortality cardiovascular
hospitalization
All-cause mortality heart failure
hospitalization
All-cause mortality
0
0.4
0.8
1.2
1.6
2
Favors carvedilol
Favors placebo
Mean duration 10.5 months. Packer M. Presentation
at AHA 2000.
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The NO Paradigm in HF
A System Out of Balance in African Americans?
Vasoconstricting and Growth Promoting
Vasodilating and Growth Inhibiting

• Norepinephrine
• Angiotensin II
• Endothelins
• Arginine vasopressin
• Aldosterone

• Natriuretic peptides
• Bradykinin
• NO

Improve Hemodynamics, Prevent Remodeling
Worsen Hemodynamics, Progressive Remodeling
Adapted from Anand and Chugh. Curr Opin
Cardiol. 199712251.
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Trial Summary
A-HeFT

• Trial in 1100 African American CHF patients
• All patients on standard care and randomized to
  placebo or hydralazine/ isosorbide dinitrate.
  Titration to 2 tablets TID 225 mg
  hydralazine/120 mg isosorbide dinitrate
• Patients followed for at least 6 months
• Primary end point combined score of mortality,
  hospitalization, and QOL
• 150 clinical sites

www.nitromed.com
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Criteria
A-HeFT
Inclusion criteria

• Stable CHF NYHA Class III-IV
• Symptomatically stable on standard CHF treatment
  ß-blockers for at least 3 months
• LVEF lt35 or LVEF lt45 and a resting LVIDD gt2.9
  cm/m2 or gt6.5 cm (by ECHO)

Exclusion criteria

• Valvular disease, obstructive cardiomyopathy,
  myocarditis
• Recent MI, active CAD, cardiac surgery, PTCA
• Ventricular arrhythmia (unless treated with
  implantable defibrillator)
• Parenteral inotropic therapy within a month

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Update
A-HeFT

• The A-HeFT Trial was prematurely terminated on
  July 9, 2004 on the recommendation of the Data
  Safety Monitoring Committee and with the
  unanimous concurrence of the Steering Committee
  and the sponsor, NitroMed Inc, because of a
  significant mortality benefit in patients treated
  with hydralazine/ isosorbide dinitrate

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Trial Results
A-HeFT
Kaplan-Meier Estimates of Overall Survival
1050 African Americans with Class III to IV HF,
LVEF 24, on ACEI, BB, AA Taylor, A. L. et al. N
Engl J Med. 20043512049
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Trial Results
A-HeFT
1050 African Americans with Class III to IV HF,
LVEF 24, on ACEI, BB, AA Taylor, A. L. et al. N
Engl J Med. 20043512049.
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Heart Failure Therapy in Special Populations
Similar or Different

• How should African Americans with heart failure
  be treated?
• The treatment for patients with heart failure was
  thought to be similar, irrespective of race, but
  new data from A-HeFT suggests there may be
  important differences in treatment

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Prevalence of Diabetes Mellitus in Patients
Hospitalized with HF
N44,645 patients from 250 US hospitals
Diabetes 44.1
(18 insulin Treated DM)
No Diabetes 55.9
ADHERE Registry Patients hospitalized with heart
failure as primary diagnosis Fonarow GC et al. J
Card Fail. 200284(suppl 1)S49.
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Relationship Between Diabetesand Heart Failure
Prevalence of Diabetes US population 6-8 HF
patients 22-48
Heart Failure
Diabetes Mellitus
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Insulin Resistance inChronic Heart Failure

• Fasting Insulin
• Insulin Sensitivity
• (pmol/L) (10-5 min/pmol/L)

100
6

? 300 P.01
? 70 P.007
75
50
3

25
0
0
Heart Failure
Normal
Swan JW et al. Eur Heart J. 1994151528-1532.
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Advanced Heart Failure Associatedwith Increased
Risk of Diabetes
HR 1.70 P.05
New Onset Diabetes ()
NYHA Functional Class
BIP Trial 2616 nondiabetics at baseline, prior
MI during 7.7 years of follow-up Am J Med.
2003114271275.
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Effect of Diabetes and Heart Failureon Outcomes
in SOLVD
1.29 (1.10-1.50) P.0016
All-cause mortality
All-cause mortality or CHF hospitalization
1.52 (1.34-1.72) Plt.001
Mortality CAD Patients
1.37 (1.21-1.55) P.001
Mortality Non-CAD Patients
0.98 (0.76-1.32) P.98
0.1
1
2
Shindler DM. Am J Cardiol. 771017-1020. Dries. J
Am Coll Cardiol. 200138421-428.
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ACEI, Beta Blockers, and Aldosterone Antagonists
in Diabetic and Nondiabetic Patients with Heart
Failure

• ACE Inhibitors meta-analysis demonstrates that
  diabetics and nondiabetics benefited to similar
  degree with ACEI in HF RR 0.80 vs 1.25)
• Beta Blockers meta-analysis demonstrates that
  diabetics and nondiabetics both benefited with
  BB in HF RR 0.65 vs 0.77
• Aldosterone Antagonists In EPHESUS, both
  diabetics and nondiabetics both benefited from
  eplerenone to a similar degree

Shekelle P et al. J Am Coll Cardiol.
2003411529-38. Pitt B et al. NEJM
20033481309-1321.
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ACE Inhibitors in Diabetic andNondiabetic
Patients with Heart Failure
Shekelle P et al. J Am Coll Cardiol.
2003411529-1538.
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Beta Blockers in Diabetic and Nondiabetic
Patients with Heart Failure
Shekelle P et al. J Am Coll Cardiol.
2003411529-38.
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Metoprolol vs Carvedilol on the Risk of
New-Onset Diabetes in HF COMET
Carvedilol vs
Relative risk
95 CI
P value
Metoprolol
15
0.78
0.61 - 0.99
0.04
10
Percentage Endpoint ()
5
Metoprolol
Carvedilol
0
0
1
2
3
4
5
Time (years)
Number at risk
Metoprolol
991
879
764
626
221
Carvedilol
1014
908
827
705
254
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Diabetic Therapy for Diabetic Patients with Heart
Failure Potential for Harm

• Insulin associated with increased sympathetic
  nervous system activation, increased vascular
  resistance, increased cardiac and vascular
  hypertrophy, and endothelial dysfunction
• Sulfonylureas abolish ischemic preconditioning
  and leave the myocardium more susceptible to
  injury. Also by further increasing insulin levels
  these agents could worsen outcome
• Metformin renal dysfunction common in heart
  failure raises concerns regarding the risk of
  lactic acidosis
• Thiazolidinediones potential for weight gain,
  edema, and worsened heart failure

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Incidence of Heart Failure Associated with
Anti-Diabetic Therapies
Insulin vs Oral HF HR 2.5 Plt0.00001
N8,063
CHF Rate / year per 1000
Adjusted Risk Rates age, sex, duration, HTN,
renal fxn, Hb A1c
Nichols. Diabetes Metab Res Rev. 2004.
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Insulin-Dependent Diabetes Is Associated with
Increased Mortality in Patients with Advanced HF
DM, No Insulin
No DM
DM, Insulin
P0.0002
624 patients with advanced HF, systolic
dysfunction Smooky and Fonarow. Submitted HFSA
2003.
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Heart Failure in Diabetes

• Diabetic patients are at elevated risk for HF
• Combined neurohormonal blockade with the use of
  ACE inhibitors, aldosterone antagonists,
  and?-blockers is essential in the treatment of
  the diabetic patient with HF
• The optimal treatment for glycemic control in
  patients with diabetes and heart failure has not
  been well studied, and urgent clinical
  investigations are needed

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Heart Failure Therapy in Special Populations
Similar or Different?

• How should older, female, African Americans, and
  diabetic patients with heart failure be treated?
• The treatment for patients with heart failure
  should in general be similar, and variations
  other than as indicated by individual patient
  presentation are generally not appropriate
• New data suggest that African Americans with HF
  benefit from hydralazine-isosorbide dinitrate