Improving Outcomes in Heart Failure: New Insights From Vascular Biology

1
Improving Outcomes in Heart Failure New
Insights From Vascular Biology
2
Heart Failure A Public Health Concern
3
20 Lifetime risk for HF after age 40
Framingham Heart Study
Men
Women
25
25
20
20
15
15
Cumulative risk ()
10
10
5
5
0
0
0
40
50
50
60
70
80
90
40
50
50
60
70
80
90
Attained age (years)
Lifetime risk for HF for given index age is
cumulative through age 94 years
Lloyd-Jones DM et al. Circulation.
20021063068-72.
4
Hypertension is the No. 1 risk factor for HF
Framingham Heart Study
60
40
Population-attributable risk ()
20
0
HTN
MI
Angina
VHD
LVH
Diabetes
Men
Women
VHD valvular heart disease
Levy D at al. JAMA. 19962751557-62.
5
Diabetes A frequent comorbidity with HF

• Framingham data show ? HF in diabetic adults age
  45 to 74 years 2x ? in men 5x ? in women
• Medicare sample of diabetic adults age 65 years
  (19941999) HF prevalence in 1994 22.4
  Annual HF incidence 7.9 Similar incidence
  by sex and race Significant ? with age and
  diabetes-related comorbidities
• National registry of gt100,000 patients
  hospitalized with HF (mean age 72.4 years)
  44 had diabetes

Bell DSH. Diabetes Care. 2003262433-41. Bertoni
AG et al. Diabetes Care. 200427699-703. Adams
KF et al. Am Heart J. 2005149209-16.
6
Diabetes is the No. 1 risk factor for HF in
women with coronary disease
HERS study
Diabetes
3.1
Atrial fibrillation
2.9
Myocardial infarction gt1 event
2.5
Creatinine clearance lt40
2.3
Systolic BP 140
2.1
Current smoking
1.9
BMI gt35
1.9
Left bundle branch block
1.6
LV hypertrophy
1.5
0
0.5
1
1.5
2
2.5
3
3.5
Adjusted hazard ratio
Bibbins-Domingo K Jr et al. Circulation.20041101
424-30.
7
Increasing risk for HF in women with CHD Impact
of diabetes, renal insufficiency, obesity
HERS study 2391 women with CHD and no HF at
baseline
14
12.8
12
10
Annual HF incidence ()
8
7.0
6
4
2.8
2
1.2
0
CHD
CHD DM
CHD DM BMI gt36
CHD DM CrCl lt42.8
CrCl (ml/min) creatinine clearance
Bibbons-Domingo K et al. Circulation.20041101424
-30.
8
Heart Failure Pathophysiology
9
Important pathophysiologic mechanisms in HF (1)
Cardiac abnormalities
Functional
Structural

• Coronary arteries
• Obstruction
• Inflammation

• Left ventricular chamber
• Remodeling
• Dilation
• Increased sphericity
• Aneurysmal dilatation or wall
  thinning Concentric hypertrophy

• Myocardium or myocyte
• Myocardial relaxation
• Abnormal excitation- contraction coupling
• ?-Adrenergic desensitization
• Hypertrophy
• Necrosis
• Fibrosis
• Apoptosis

• Mitral regurgitation
• Intermittent ischemia or hibernating myocardium
• Induced arterial and ventricular arrhythmias
• Altered ventricular interaction

Modified from Jessup M, Brozena S. N Engl J Med.
20033482007-18.
10
Important pathophysiologic mechanisms in HF (2)
Biologically active tissue and circulating
substances

• RAAS
• SNS (norepinephrine)
• Vasodilators (bradykinin, nitric oxide,
  prostaglandins)

• Natriuretic peptides
• Cytokines (endothelin, tumor necrosis factor,
  interleukins)
• Vasopressin
• Matrix metalloproteinases

Jessup M, Brozena S. N Engl J Med.
20033482007-18.
11
Important pathophysiologic mechanisms in HF (3)
Patient factors

• Coexisting conditions
• Hypertension
• Diabetes
• Renal disease
• Coronary artery disease
• Anemia
• Obesity
• Sleep apnea
• Depression

• Genetics, ethnicity, sex
• Age
• Use of alcohol, tobacco, toxic drugs

Jessup M, Brozena S. N Engl J Med.
20033482007-18.
12
Neurohormonal model of HF
Injury to myocytes and extracellular matrix

• Neurohormonal activation
• RAAS, SNS
• Increased cytokine expression
• Immune and inflammatory changes
• Altered fibrinolysis

• Oxidative stress
• Apoptosis
• Altered gene expression
• Energy starvation

Ventricular remodeling
Electrical, vascular, renal, pulmonary muscle,
and other effects
Heart failure
McMurray J, Pfeffer MA. Circulation.
20021052099-106.
13
Diabetes pathogenesis accelerates HF
Diabetes
Activated RAAS
Activated sympathoadrenal system
Hyperglycemia
Activation of protein kinase C
Cardiac fibrosis
Cardiomyocyte death
Decreased intracellular calcium removal
Decreased myocardial contractile strength
Diastolic dysfunction
Systolic dysfunction
Heart failure
Kirpichnikov D et al. J Card Fail. 20039333-44.
14
RAAS in CV continuum Pivotal role of AT1
receptors in the failing heart
Angiotensinogen
Bradykinin/Kinins
Renin
Angiotensin I
Degradation
ACE
Angiotensin II
AT2 receptor
B1/B2 receptor
AT1 receptor
NO
? Clinical significance
Reactive oxygen species Pro-inflammatory
process Vasoconstriction Cellular
growth/proliferation Apoptosis Neurohormonal
activation
Vasodilation Growth inhibition Apoptosis
Adapted from Wassmann S, Nickenig G. Eur Heart J
Suppl. 20046(suppl H)H3-9.
15
Primary targets of treatment in HF
Jessup M, Brozena S. N Engl J Med.
20033482007-18.
16
Angiotensin receptor blockade in the CVD
continuum
Coronary heart disease
ARB
Plaque rupture
ARB
?
Atherosclerosis
ARB
?
Myocardial infarction
Dilation/ Remodeling
Endothelial dysfunction
ARB
?
ARB
?
?
Heart failure
ARB
?
End-stage heart failure
Risk factors
Hypertension Hyperlipidemia Diabetes
Wassmann S, Nickenig G. Eur Heart J Suppl.
20046(suppl H)H3-9.
17
Clinical Trial Update
18
Survival studies of ?-blockade in HF
Total mortality Placebo/?-blocker
Patients (N)
Favors ?-blocker
NYHA class
EF mean
P
CIBIS-II Bisoprolol
III/IV
2647
28
228/156
0.0001
MERIT-HF Metoprolol succinate CR/XL
II-IV
3991
28
217/145
0.00009
COPERNICUS Carvedilol
III/IV
2289
20
190/130
0.00013
8927
635/431
All pooled
0.5
0.0
1.0
Relative risk and 95 CI
CIBIS-II Investigators. Lancet.
19993539-13. MERIT-HF Study Group. Lancet.
19993532001-7. Packer M et al. N Engl J Med.
20013441651-8.
not recorded in COPERNICUS, but placebo
mortality indicates III/IV
19
MERIT-HF Metoprolol succinate CR/XL lowers risk
of hospitalization with/without diabetes
NYHA III/IV, EF lt25
All randomized
Diabetes
No diabetes
Diabetes
No diabetes
70
50
50
Total hospitaliz/patient-yrs ()
26
25
30
25
16
15
13
9
10
53 P 0.0087
44 P 0.0039
37 P 0.0026
35 P 0.0002
Metoprolol succinate CR/XL (n 495)
Placebo (n 490)
Deedwania PC et al. Am Heart J. 2005149159-67.
20
MERIT-HF Benefit of ?-blockade with/without
diabetes
Events (n)
Favors metoprolol succinate CR/XL
Favorsplacebo
Metoprolol succinate CR/XL
All-cause mortality
Placebo
145
All patients randomized
217
50
Diabetes
61
14
Diabetes, severe HF
24
95
No diabetes
156
31
No diabetes, severe HF
48
Hospitalization for CHF
200
All patients randomized
294
72
Diabetes
108
20
Diabetes, severe HF
40
No diabetes
128
186
40
No diabetes, severe HF
64
0.0
1.0
Relative risk (95 CI)
Severe HF NYHA class III/IV, EFlt0.25
Deedwania PC et al. Am Heart J. 2005149159-67.
21
Pooled HF trials Effect of ?-blockade on
survival in diabetic patients
Total (n) randomized
Deaths (n) Placebo/?-blockade
312
Diabetes
CIBIS II
33/27
No diabetes
2335
195/129
2647
All
228/156
MERIT-HF
985
61/50
Diabetes
3006
156/95
No diabetes
3991
217/145
All
COPERNICUS
Diabetes
589
1700
No diabetes
190/130
2289
All
All 3 studies
Diabetes
1886
7041
No diabetes
All
635/431
8927
0.0
1.0
1.8
Relative risk (95 CI)
Deedwania PC et al. Am Heart J. 2005149159-67.
22
GEMINI Design
Glycemic Effects in diabetes Mellitus
carvedilol-metoprolol comparison IN
hypertensIves study
Objective Compare effects of ?-blockers with
different pharmacologic properties on glycemic
and metabolic control in patients with diabetes
and hypertension receiving RAAS
blockade Participants 1235 patients
Randomized to treatment Carvedilol 6.25 mg to
25 mg bid (n 498) or Metoprolol tartrate 50 mg
to 200 mg bid (n 737) Follow-up 35 weeks
Bakris GL et al. JAMA. 20042922227-36.
23
GEMINI Change in HbA1c and insulin sensitivity
Endpoint (mean ?)
Bakris GL et al. JAMA. 20042922227-36.
24
RESOLVD substudy Effect of metoprolol succinate
CR/XL on glucose and insulin
Randomized Evaluation of Strategies fOr Left
Ventricular Dysfunction

• 247 patients with heart failure
• Mean LVEF 28
• 18 female
• 26 with diabetes
• At 17 weeks, patients taking enalapril ?
  candesartan were randomized to
  Metoprolol succinate CR/XL 200
  mg/d (n 130) or Placebo (n 117)
• Blood samples analyzed at 17 weeks and after 43
  weeks

Demers C et al. Canadian Cardiovascular
Congress 2004. Calgary.
Phase 2 regimen
25
RESOLVD substudy No effect on glucose and
insulin with metoprolol succinate CR/XL
17 weeks
43 weeks
Phase 2 Start metoprolol succinate CR/XL P
NS vs placebo
Demers C et al. Canadian Cardiovascular
Congress 2004. Calgary.
26
Implications for ?-blockade in diabetes and HF

• HF is a frequent, often fatal complication of
  diabetes
• ?-Blockers are safe and well tolerated by
  patients with HF and diabetes
• ?-Blockade benefits diabetic patients by
  decreasing hospitalizations for HF and improving
  survival
• It is time to remove existing barriers for use of
  ?-blockers in patients with HF and diabetes

Deedwania PC et al. Am Heart J. 2005149159-67.
27
MERIT-HF Mortality benefit of ?-blockade in the
elderly
All-cause mortality
Sudden death
20
12
Risk reduction 37
Risk reduction 43
Placebo
Placebo
P 0.0008
9
15
P 0.0032
Metoprolol succinate CR/XL
Metoprolol succinate CR/XL
Patients
Patients
10
6
5
3
HF mortality
0
0
6
Risk reduction 61
Placebo
3
6
9
12
15
18
0
3
6
9
12
15
18
0
Months
Months
P 0.0005
4
Patients
Metoprolol succinate CR/XL
2
0
3
6
9
12
15
18
0
Deedwania PC et al. Eur Heart J. 2004251300-9.
Months
N 1982 age 65 years
28
Meta-analysis ?-Blockade improves survival in
elderly HF patients
Placebo better
Hazard ratio
?-blocker better
0.75 (0.580.98)
COPERNICUS
0.45 (0.240.86)
Carvedilol (U.S.)
0.70 (0.490.99)
CIBIS-II
0.70 (0.520.95)
MERIT-HF
BEST
0.91 (0.781.05)
0.76 (0.640.90)
Overall
P 0.002
1
1
10
Risk ratio (95 CI)
Dulin BR et al. Am J Cardiol.200595896-8.
29
SENIORS Design
Study of the Effects of Nebivolol Intervention on
Outcomes and Rehospitalization in Seniors with
heart failure

• 2128 patients with HF or LVEF 35
• 70 years of age (mean, 76 years)
• Randomly assigned to
• - Nebivolol titrated to 10 mg once daily over
  16-week maximum (n 1067)
• - Placebo (n 1061)
• Primary outcome Composite of all-cause mortality
  or CV hospital admission (time to first event)
• Follow-up median 21 months

Flather MD et al. Eur Heart J. 200526215-25.
30
SENIORS Primary and secondary outcomes
All-cause mortality or CV hospital admission
(primary outcome)
All-cause mortality (main secondary outcome)
100
100
HR 0.88 (0.711.08) P 0.214
90
90
HR 0.86 (0.740.99) P 0.039
Nebivolol
Event- free survival ()
80
80
Placebo
Nebivolol
70
70
60
60
Placebo
50
50
0
6
12
18
24
30
0
6
12
18
24
30
Time (months)
Time (months)
No. of events
169 (15.8) 192 (18.1)
Nebivolol 332 (31.1) Placebo
375 (35.3)
Flather MD et al. Eur Heart J. 200526215-25.
HR hazard ratio
31
SENIORS Clinical relevance

• Confirms data indicating ?-blockade benefits
  elderly HF patients
• Extends evidence for benefit of ?-blockade to a
  broad range of elderly patients (age gt70 years)
  with HF, including those with mild or preserved
  LV function
• As in previous large trials, both all-cause
  mortality and CV hospital admissions show a
  similar and consistent effect with ?-blockade

Flather MD et al. Eur Heart J. 200526215-25.
32
Benefit of ?-blockade on mortality in urban
patients with HF
N 551 62 African American, 20 White, 15
Hispanic NYHA class III/IV HF No ?-blocker group
60 ?-blocker group 45
20
17
No ?-blockers
Death at 1 year ()
10
P lt 0.001
4
?-blockers
0
0
6
12
Months
No ?-blocker 132 115 100 ?-blocker 239 229 21
2
Estep JD et al. Am Heart J. 2004148958-63.
33
Not all ?-blockers are the same
Generic name
Brand name
AB-rated generic equiv available
Properties
Dose for HF
? see prescribing information
COPERNICUS other trials 50 mg bid for gt75 kg
34
Metoprolol tartrate vs metoprolol succinate
CR/XL Significant pharmacokinetic differences
Three-way crossover in patients with HF N 15
300
Metoprolol succinate CR/XL 200 mg x 1
200
Plasmaconcentration (mmol/L)
Metoprolol tartrate 50 mg x 3
100
Metoprolol succinate CR/XL 100 mg x 1
0
14
22
08
08
Time (h)
Metoprolol succinate CR/XL 100 mg Metoprolol
succinate CR/XL 200 mg Metoprolol tartrate 50 mg
Metoprolol tartrate 50 mg
Andersson B et al. J Card Fail. 20017311-7.
35
Effect of metoprolol succinate CR/XL vs atenolol
on exercise heart rate/SBP over 24 h
N 10 healthy men
Systolic BP
Exercise heart rate
160
190
Placebo
Placebo
180
140
Meanexercise SBP (mm Hg)
Meanexercise heart rate (bpm)
170
Atenolol 50 mg
120
Atenolol 50 mg
160
Metoprolol succinate CR/XL 100 mg
Metoprolol succinate CR/XL 100 mg
100
150
0
0
0
2
8
12
24
4
0
2
8
12
24
4
Time (hours)
Time (hours)
Blomqvist I et al. Eur J Clin Pharmacol.
198833(suppl)S19-24.
36
Recommended ACEI doses do not completely halt
Ang II formation in HF
42 HF patients on 40 mg long-acting ACEI
(fosinopril, lisinopril, enalapril) or captopril
150 mg
25


20
ACEI
? Radial artery systolic pressure (mm Hg)


15
10
ACEI valsartan
5
0
100
0
200
10
Angiotensin I (ng/Kg)
P lt 0.05 vs after valsartan P lt 0.05 vs 10
ng/kg Ang I
Jorde UP et al. Circulation. 2000101844-6.
37
CHARM Program 3 Component trials comparing
candesartan with placebo
Target dose, candesartan 32 mg
Primary outcome CV death or CHF hospitalization
Overall trial All-cause death
CHARM- Alternative
CHARM- Added
CHARM- Preserved
n 2028 LVEF 40 ACE inhibitor intolerant
n 3023 LVEF gt40 ACE inhibitor treated/not
treated
n 2548 LVEF 40 ACE inhibitor treated
Median follow-up, 37 months
Pfeffer MA et al. Lancet. 2003362759-66. Granger
CB et al. Lancet. 2003362772-6. McMurray JJV
et al. Lancet. 2003362767-71. Yusuf S et al.
Lancet. 2003362777-81.
38
CHARM Program Reduction in mortality and
morbidity
CV death or HF hospitalization
All-cause mortality
Alternative (LVEF 40 ACEI intolerant)
Added (LVEF 40 ACEI treated)
Preserved (LVEF gt40 ACEI treated/not treated)
Overall
0.9
0.7
0.8
0.6
1.2
1.0
1.1
1.1
1.0
0.8
0.9
0.7
1.2
Adjusted hazard ratio P heterogeneity 0.37
Adjusted hazard ratio P heterogeneity 0.33
Pfeffer MA et al. Lancet. 2003362759-66.
39
CHARM-Overall CV death and non-CV
deathSecondary endpoints
35
13 Relative risk reduction(95 CI 422) P
0.006
25
CV death
20
Patients
15
10
Non-CV death
5
P 0.45
0
2.0
3.0
0.0
1.0
3.5
Years
Number at risk
Candesartan 3803 3563 3271 2215
761 Placebo 3796 3464 3170 2157 743
Pfeffer MA et al. Lancet. 2003362759-66.
40
CHARM-Overall Reduction in mortality and
nonfatal MI with candesartan
Events (n) Placebo/candesartan
Risk reduction
P
Sudden death
344/299
15
0.036
HF death
260/209
22
0.008
CV death
769/691
12
0.012
Nonfatal MI
148/116
23
0.032
Nonfatal MI/CV death
868/775
21
0.004
All deaths
945/886
9
0.055
0.5
0.6
0.7
9.0
8.0
1.0
0.5
Solomon SD et al. Circulation. 20041102180-83. D
emers C et al. Circulation. 2004110(suppl)Abstra
ct.
41
CHARMLow LVEF trials Risk reductions at 1 and
2 years with candesartan
LVEF 40
CV death/HF hospitalization
All-cause mortality
0
10
20
20
Reduction
23
P 0.001
P lt 0.001
30
30
33
P lt 0.001
1 year
P 0.001
40
2 years
50
Young JB et al. Circulation. 20041102618-26.
42
CHARM Program Outcomes overview
Candesartan vs placebo
Gleiter CH et al. Cardiovasc Drug Rev.
200422263-84.
statistically significant
43
CHARM-Overall Reduction in new-onset diabetes
n new-onset diabetes N total patients
Pfeffer MA et al. Lancet. 2003362759-66.
44
VALIANT Design

• 14,800 patients with acute MI HF/LV dysfunction
• Receiving conventional therapy
• Randomly assigned (0.5 days to 10 days after
  acute MI) Valsartan 160 mg bid (n 4909)
  Valsartan 80 mg bid captopril 25 mg tid (n
  4885) Captopril 50 mg tid (n 4909)
• Primary outcome death from any cause
• Follow-up median 24.7 months

Pfeffer MA et al. N Engl J Med. 20033491893-906.
45
VALIANT Treatments show similar effect on
outcome
Death from any cause
Combined CV endpoint
0.4
0.4
0.3
0.3
Probability of event
0.2
0.2
0.1
0.1
0.0
0.0
0
6
12
18
24
30
36
6
12
18
24
30
36
0
Months
Months
Captopril
Valsartan/captopril
Valsartan
CV death, reinfarction, or hospitalization
for HF
Pfeffer MA et al. N Engl J Med. 20033491893-906.
46
VALIANT Poorer 1-year outcomes in patients with
new-onset or previous diabetes
All-cause mortality
Adverse CV events
0.4
0.4
Previous DM
0.3
0.3
New DM
0.2
0.2
Probability of event
Previous DM
No DM
New DM
0.1
0.1
No DM
0.0
0.0
3
6
9
12
0
3
6
9
12
0
Months
Months
Previous vs new diabetes diagnosis Previous vs no
diabetes New vs no diabetes diagnosis
P 0.43 P lt 0.001 P lt 0.001
P lt 0.005 P lt 0.001 P lt 0.001
Aguilar D et al. Circulation. 20041101572-8.
47
Clinical implications of CHARM and VALIANT

• In HF patients and in patients with acute MI and
  LV dysfunction, evidence supports ARBs as
  alternative to ACEIs (in ACEIintolerant
  patients) Benefit from addition of ARBs to
  ACEI-based regimens
• ARBs and ACEIs similarly reduce all-cause
  mortality and HF hospitalizations in patients
  with HF or high-risk MI
• Discharge prescription of ACEI or ARB meets new
  Medicare/Medicaid quality performance measures
  for HF/MI with LV dysfunction

Lee VC et al. Ann Intern Med. 2004141693-704. Mc
Clellen MB et al. Ann Intern Med.
2005142386-7.
ACC/AHA. www.acc.org
48
Benefit of ARB ACE inhibitor in HF
HF hospitalization
All-cause mortality
ARBACEI better
ACEI alone better
ARBACEI better
ACEI alone better
CHARM (HF)
VALIANT (post MI HF/LV dysfunction)
Val-HeFT (HF)
0.6
1.2
0.8
1.0
1.4
1.2
0.8
1.0
1.4
0.6
Voors AA, van Veldhuisen DJ. Int J Cardiol.
200497345-8.
49
ARBs in LV dysfunction Before/after CHARM and
VALIANT
Voors AA, van Veldhuisen DJ. Int J Cardiol.
200497345-8.
50
Difference in target dosing among ARB trials
Dickstein K et al. Lancet. 2002360752-60. Cohn
JN et al. N Engl J Med. 20013451667-75. Pfeffer
MA et al. N Engl J Med. 20033491893-906.
Pfeffer MA et al. Lancet. 2003362759-66. Pitt
B et al. Lancet. 20003551582-7.
51
Impact of RAAS modulation on mortality in HF
patients with renal insufficiency
Minnesota Heart Survey
Post-discharge mortality(mean follow-up 15 mo)
ACEI/ARB Rx at discharge
7
P 0.17
6
80
68
64
63
5
60
Odds ratio (95 CI)
48
4
P 0.002

40
P 0.04
3
P 0.65
20
2
1
0
90
6089
3059
lt30
0
90
6089
3059
lt30
GFR (mL/min)
GFR (mL/min)
No ACEI/ARB at discharge
ACEI and/or ARB at discharge
Berger AK et al. Circulation. 2004110 (suppl
III)III-749.
4926 patients hospitalized with HF
52
Summary
53
ACC/AHA stages of systolic HF and treatment
options
Jessup M, Brozena S. N Engl J Med.
20033482007-18.
In appropriate patients