VBWG
Improving Outcomes in
Heart Failure: New Insights
From Vascular Biology
VBWG
Heart Failure:
A Public Health Concern
VBWG
20% Lifetime risk for HF after age 40
Framingham Heart Study
Men
Cumulative
risk (%)
25
25
20
20
15
15
10
10
5
5
0
0
40
50
60
70
80
90
Women
40
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. 2002;106:3068-72.
Hypertension is the No. 1 risk factor for HF
VBWG
Framingham Heart Study
60
40
Populationattributable
risk (%)
20
0
Hazard ratio
HTN
MI
Angina
VHD
LVH
Diabetes
M
2.1
6.3
1.4
2.5
2.2
1.8
W
3.3
6.0
1.7
2.1
2.8
3.7
Men
VHD = valvular heart disease
Women
Levy D at al. JAMA. 1996;275:1557-62.
Diabetes: A frequent comorbidity with HF
VBWG
• 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 (1994–1999):
– 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 >100,000 patients hospitalized with HF
(mean age 72.4 years)
– 44% had diabetes
Bell DSH. Diabetes Care. 2003;26:2433-41.
Bertoni AG et al. Diabetes Care. 2004;27:699-703.
Adams KF et al. Am Heart J. 2005;149:209-16.
VBWG
Diabetes is the No. 1 risk factor
for HF in women with coronary disease
HERS study
Diabetes
3.1
2.9
Atrial fibrillation
Myocardial infarction >1 event
2.5
Creatinine clearance <40
2.3
2.1
Systolic BP ≥140
Current smoking
1.9
BMI >35
1.9
Left bundle branch block
1.6
1.5
LV hypertrophy
0
0.5
1
1.5
2
2.5
3
3.5
Adjusted hazard ratio
Bibbins-Domingo K Jr et al. Circulation.2004;110:1424-30.
Increasing risk for HF in women with CHD:
Impact of diabetes, renal insufficiency, obesity
VBWG
HERS study; 2391 women with CHD and no HF at baseline
14
12.8
12
10
Annual
8
HF
incidence
6
(%)
7.0
4
2
2.8
1.2
0
CHD
CrCl (ml/min) = creatinine clearance
CHD + DM
CHD + DM
+ BMI >36
CHD + DM
+ CrCl <42.8
Bibbons-Domingo K et al. Circulation.2004;110:1424-30.
VBWG
Heart Failure
Pathophysiology
VBWG
Important pathophysiologic mechanisms in
HF (1)
Cardiac abnormalities
Structural
Myocardium or myocyte
Left ventricular chamber
• Myocardial relaxation
• Abnormal excitationcontraction coupling
• -Adrenergic
desensitization
• Hypertrophy
• Necrosis
• Fibrosis
• Apoptosis
• Remodeling
– Dilation
– Increased sphericity
– Aneurysmal dilatation
or wall thinning
– Concentric hypertrophy
Functional
Coronary arteries
• Obstruction
• Inflammation
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. 2003;348:2007-18.
VBWG
Important pathophysiologic mechanisms in
HF (2)
Biologically active tissue
and circulating substances
• RAAS
• Natriuretic peptides
• SNS (norepinephrine)
• Cytokines (endothelin, tumor
necrosis factor, interleukins)
• Vasodilators (bradykinin, nitric oxide,
prostaglandins)
• Vasopressin
• Matrix metalloproteinases
Jessup M, Brozena S. N Engl J Med. 2003;348:2007-18.
VBWG
Important pathophysiologic mechanisms in
HF (3)
Patient factors
• Genetics, ethnicity, sex
• Age
• Use of alcohol, tobacco,
toxic drugs
Coexisting conditions
• Hypertension
• Diabetes
• Renal disease
• Coronary artery disease
• Anemia
• Obesity
• Sleep apnea
• Depression
Jessup M, Brozena S. N Engl J Med. 2003;348:2007-18.
VBWG
Neurohormonal model of HF
Injury to myocytes and extracellular matrix
• Neurohormonal activation
– RAAS, SNS
• Increased cytokine
expression
• Oxidative stress
Ventricular remodeling
• Apoptosis
• Altered gene expression
• Immune and
inflammatory changes
• Energy starvation
• Altered fibrinolysis
Electrical, vascular, renal,
pulmonary muscle, and other effects
Heart failure
McMurray J, Pfeffer MA.
Circulation. 2002;105:2099-106.
Diabetes pathogenesis accelerates HF
VBWG
Diabetes
Activated
sympathoadrenal
system
Activated
RAAS
Hyperglycemia
Cardiomyocyte
death
Cardiac
fibrosis
Activation of
protein kinase C
Decreased myocardial
contractile strength
Decreased intracellular
calcium removal
Diastolic
dysfunction
Systolic
dysfunction
Heart failure
Kirpichnikov D et al. J Card Fail. 2003;9:333-44.
VBWG
RAAS in CV continuum: Pivotal role
of AT1 receptors in the failing heart
Angiotensinogen
Renin
Bradykinin/Kinins
Angiotensin I
Degradation
ACE
Angiotensin II
AT1 receptor
AT2 receptor
Reactive oxygen species
Pro-inflammatory process
Vasoconstriction
Cellular growth/proliferation
Apoptosis
Neurohormonal activation
? Clinical significance
B1/B2 receptor
NO
Vasodilation
Growth inhibition
Apoptosis
Adapted from Wassmann S, Nickenig G.
Eur Heart J Suppl. 2004;6(suppl H):H3-9.
Primary targets of treatment in HF
VBWG
Jessup M, Brozena S. N Engl J Med. 2003;348:2007-18.
VBWG
Angiotensin receptor blockade
in the CVD continuum
ARB
Coronary heart
disease

ARB

Plaque rupture
ARB
Atherosclerosis
ARB

Myocardial
infarction
Endothelial
dysfunction
Dilation/
Remodeling
ARB
Heart failure
ARB

Hypertension
Hyperlipidemia
Diabetes
Risk factors
End-stage
heart failure
Wassmann S, Nickenig G.
Eur Heart J Suppl. 2004;6(suppl H):H3-9.
VBWG
Clinical Trial Update
VBWG
Survival studies of -blockade in HF
Patients
(N)
Total mortality
Placebo/
-blocker
NYHA
class
EF
mean
P
CIBIS-II
Bisoprolol
2647
228/156
III/IV
28%
0.0001
MERIT-HF
Metoprolol succinate CR/XL
3991
217/145
II-IV
28%
0.00009
COPERNICUS
Carvedilol
2289
190/130
III/IV*
20%
0.00013
All pooled
8927
635/431
Favors
-blocker
0.0
0.5
1.0
Relative risk and 95% CI
*not recorded in COPERNICUS, but
placebo mortality indicates III/IV
CIBIS-II Investigators. Lancet. 1999;353:9-13.
MERIT-HF Study Group. Lancet. 1999;353:2001-7.
Packer M et al. N Engl J Med. 2001;344:1651-8.
VBWG
MERIT-HF: Metoprolol succinate CR/XL
lowers risk of hospitalization with/without diabetes
All randomized
Diabetes
NYHA III/IV, EF <25%
No diabetes
Diabetes
No diabetes
70
50
50
Total #
hospitaliz/ 30
patient-yrs
(%)
10
25
25
16
26
15
13
9
–37%
–35%
–53%
–44%
P = 0.0026
P = 0.0002
P = 0.0087
P = 0.0039
Placebo
(n = 490)
Metoprolol succinate CR/XL
(n = 495)
Deedwania PC et al. Am Heart J. 2005;149:159-67.
MERIT-HF: Benefit of -blockade
VBWG
with/without diabetes
Events (n)
All-cause mortality
Placebo
Metoprolol
succinate CR/XL
All patients randomized
217
145
Diabetes
61
50
Diabetes, severe HF
24
14
No diabetes
156
95
No diabetes, severe HF
48
31
All patients randomized
294
200
Diabetes
108
72
Diabetes, severe HF
40
20
No diabetes
186
128
No diabetes, severe HF*
64
40
Favors metoprolol
succinate CR/XL
Favors
placebo
Hospitalization for CHF
0.0
1.0
Relative risk (95% CI)
*Severe HF = NYHA class III/IV, EF<0.25
Deedwania PC et al. Am Heart J. 2005;149:159-67.
VBWG
Pooled HF trials: Effect of -blockade
on survival in diabetic patients
Total (n)
randomized
Deaths (n)
Placebo/-blockade
CIBIS II
Diabetes
No diabetes
All
312
2335
2647
33/27
195/129
228/156
MERIT-HF
Diabetes
No diabetes
All
985
3006
3991
61/50
156/95
217/145
COPERNICUS
Diabetes
No diabetes
All
589
1700
2289
190/130
Diabetes
No diabetes
All
1886
7041
8927
635/431
All 3 studies
0.0
1.0
1.8
Relative risk (95% CI)
Deedwania PC et al. Am Heart J. 2005;149:159-67.
VBWG
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:
Follow-up:
Carvedilol 6.25 mg to 25 mg bid (n = 498) or
Metoprolol tartrate 50 mg to 200 mg bid (n = 737)
35 weeks
Bakris GL et al. JAMA. 2004;292:2227-36.
VBWG
GEMINI: Change in HbA1c
and insulin sensitivity
Metoprolol tartrate
Endpoint
(mean )
HbA1c
Insulin
sensitivity
Carvedilol
% (SD)
P
% (SD)
P
0.15 (0.04)
<0.001
0.02 (0.04)
0.65
–2.0
0.48
–9.1
0.004
Bakris GL et al. JAMA. 2004;292:2227-36.
RESOLVD substudy: Effect of metoprolol
succinate CR/XL on glucose and insulin
VBWG
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
*Phase 2 regimen
Demers C et al. Canadian Cardiovascular
Congress; 2004. Calgary.
VBWG
RESOLVD substudy: No effect on glucose
and insulin with metoprolol succinate CR/XL
17 weeks*
43 weeks
Glucose
(mmol/L)
Insulin
(mmol/L)
Glucose
Insulin
(mmol/L)
(mmol/L)
Metoprolol
succinate
CR/XL
8.26
107
8.31†
108†
Placebo
8.28
116
8.38
139
*Phase 2: Start metoprolol succinate CR/XL
†P = NS vs placebo
Demers C et al. Canadian Cardiovascular
Congress; 2004. Calgary.
Implications for -blockade in diabetes
and HF
VBWG
• 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. 2005;149:159-67.
VBWG
MERIT-HF: Mortality benefit
of -blockade in the elderly
Sudden death
All-cause mortality
20
12
Risk reduction
43%
Placebo
9
Metoprolol succinate CR/XL
Metoprolol
succinate
CR/XL
%
Patients 10
3
Placebo
P = 0.0008
15
P = 0.0032
%
Patients 6
Risk reduction
37%
5
HF mortality
0
0
3
6
9 12 15 18
Months
6
0
Placebo
Risk
reduction
61%
P = 0.0005
4
%
Patients
0
3
6
9 12 15 18
Months
Metoprolol succinate CR/XL
2
0
0
N = 1982 age ≥65 years
3
6
9 12 15 18
Months
Deedwania PC et al. Eur Heart J.
2004;25:1300-9.
Meta-analysis: -Blockade improves
survival in elderly HF patients
-blocker better Placebo better
VBWG
Hazard ratio
COPERNICUS
0.75 (0.58–0.98)
Carvedilol (U.S.)
0.45 (0.24–0.86)
CIBIS-II
0.70 (0.49–0.99)
MERIT-HF
0.70 (0.52–0.95)
BEST
0.91 (0.78–1.05)
Overall
0.76 (0.64–0.90)
P = 0.002
–1
1
10
Risk ratio (95% CI)
Dulin BR et al. Am J Cardiol.2005;95:896-8.
VBWG
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. 2005;26:215-25.
VBWG
SENIORS: Primary and secondary outcomes
All-cause mortality or
CV hospital admission
(primary outcome)
100
All-cause mortality
(main secondary outcome)
HR 0.88 (0.71–1.08)
100
P = 0.214
90
HR 0.86 (0.74–0.99)
Event- 80
free
survival 70
(%)
60
P = 0.039
90
Nebivolol
80
Nebivolol
Placebo
50
Placebo
70
60
50
0
6
12
18
24
Time (months)
30
0
6
12
18
24
Time (months)
No. of events:
Nebivolol
332 (31.1%)
169 (15.8%)
Placebo
192 (18.1%)
HR = hazard ratio
375 (35.3%)
30
Flather MD et al. Eur Heart J. 2005;26:215-25.
SENIORS: Clinical relevance
VBWG
• Confirms data indicating -blockade benefits
elderly HF patients
• Extends evidence for benefit of -blockade to a
broad range of elderly patients (age >70 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. 2005;26:215-25.
VBWG
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 < 0.001
4%
-blockers
0
0
6
12
Months
No -blocker
-blocker
132
239
115
229
100
212
Estep JD et al. Am Heart J. 2004;148:958-63.
Not all -blockers are the same
Generic
name
Brand
name*
Properties
VBWG
AB-rated generic
equiv available Dose for HF
Atenolol
Tenormin
1 selective
Yes
Not FDAapproved for HF
Bisoprolol
Zebeta
1 selective
N/A
Not FDAapproved for HF
Metoprolol
tartrate
Lopressor
or generic
1 selective
Yes
Not FDAapproved for HF
Metoprolol
succinate
CR/XL
TOPROL-XL
1 selective
No
200 mg qd
Carvedilol
Coreg
Non-selective
(1, 1, 2)
No
25 mg bid†
Labetalol
Normodyne
Non-selective
(1, 1, 2)
Yes
Not FDAapproved for HF
†COPERNICUS;
other trials 50 mg bid for >75 kg
* see prescribing information
Metoprolol tartrate vs metoprolol succinate CR/XL:
Significant pharmacokinetic differences
VBWG
Three-way crossover in patients with HF; N = 15
300
Metoprolol succinate CR/XL
200 mg x 1
200
Plasma
concentration
(mmol/L)
100
Metoprolol succinate CR/XL
100 mg x 1
0
08
Metoprolol succinate CR/XL 100 mg
Metoprolol succinate CR/XL 200 mg
Metoprolol tartrate 50 mg
14
Time (h)
22
Metoprolol
tartrate
50 mg x 3
08
Metoprolol tartrate
50 mg
Andersson B et al. J Card Fail. 2001;7:311-7.
Effect of metoprolol succinate CR/XL vs
atenolol on exercise heart rate/SBP over 24 h
VBWG
N = 10 healthy men
Systolic BP
Exercise heart rate
160
190
Placebo
Placebo
180
Mean
exercise 170
SBP
(mm Hg) 160
140
Mean
exercise
heart rate 120
(bpm)
Atenolol 50 mg
Metoprolol succinate CR/XL
100 mg
Atenolol 50 mg
Metoprolol succinate CR/XL
100 mg
100
150
0
0
0 2 4
8
12
Time (hours)
24
0
2
4
8
12
24
Time (hours)
Blomqvist I et al. Eur J Clin Pharmacol. 1988;33(suppl):S19-24.
Recommended ACEI doses do not
completely halt Ang II formation in HF
VBWG
42 HF patients on 40 mg long-acting ACEI (fosinopril, lisinopril,
enalapril) or captopril 150 mg
25
*†
20

ACEI
*†
15
Radial artery
systolic pressure
10
(mm Hg)
ACEI +
valsartan
5
0
0 10
*P < 0.05 vs after valsartan
†P < 0.05 vs 10 ng/kg Ang I
100
Angiotensin I (ng/Kg)
200
Jorde UP et al. Circulation. 2000;101:844-6.
CHARM Program: 3 Component trials
comparing candesartan with placebo
VBWG
Target dose, candesartan 32 mg
Primary outcome: CV death or CHF hospitalization
Overall trial: All-cause death
CHARMAlternative
CHARMAdded
CHARMPreserved
n = 2028
n = 2548
n = 3023
LVEF ≤40%
ACE inhibitor
intolerant
LVEF ≤40%
ACE inhibitor
treated
LVEF >40%
ACE inhibitor
treated/not treated
Median follow-up, 37 months
Pfeffer MA et al. Lancet. 2003;362:759-66.
Granger CB et al. Lancet. 2003;362:772-6.
McMurray JJV et al. Lancet. 2003;362:767-71.
Yusuf S et al. Lancet. 2003;362:777-81.
CHARM Program: Reduction
in mortality and morbidity
All-cause mortality
VBWG
CV death or
HF hospitalization
Alternative
(LVEF ≤40%; ACEI intolerant)
Added
(LVEF ≤40%; ACEI treated)
Preserved
(LVEF >40%; ACEI treated/
not treated)
Overall
0.7
0.8
0.9 1.0 1.1 1.2
Adjusted hazard ratio
P heterogeneity = 0.37
0.6 0.7 0.8 0.9 1.0 1.1 1.2
Adjusted hazard ratio
P heterogeneity = 0.33
Pfeffer MA et al. Lancet. 2003;362:759-66.
CHARM-Overall: CV death and
non-CV death—Secondary endpoints
35
13% Relative risk reduction
(95% CI 4%–22%)
25
%
Patients
VBWG
P = 0.006
CV death
20
15
10
Non-CV death
5
P = 0.45
0
Years 0.0
1.0
2.0
3.0 3.5
3563
3464
3271
3170
2215 761
2157 743
Number at risk
Candesartan
Placebo
3803
3796
Pfeffer MA et al. Lancet. 2003;362:759-66.
CHARM-Overall: Reduction in mortality
and nonfatal MI with candesartan
VBWG
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
9%
0.055
945/886
0.5
0.6
0.7
8.0
9.0
1.0
0.5
Solomon SD et al. Circulation. 2004;110:2180-83.
Demers C et al. Circulation. 2004;110(suppl):Abstract.
CHARM—Low LVEF trials: Risk reductions
at 1 and 2 years with candesartan
VBWG
LVEF ≤40%
CV death/HF hospitalization
All-cause mortality
0
10
20
20
%
Reduction
P = 0.001
23
30
P < 0.001
30
P < 0.001
40
33
P = 0.001
1 year
2 years
50
Young JB et al. Circulation. 2004;110:2618-26.
CHARM Program: Outcomes overview
VBWG
Candesartan vs placebo
Parameter
Follow-up (months)
CV deaths (%)
HF hospitalization (%)
Combined
endpoint (%)
NNT/year to prevent
1 CV death/HF
hospitalization
*statistically significant
CHARM
Added
CHARM
Alternative
CHARM
Preserved
CHARM
Overall
41
34
37
38
23.7 vs 27.3*
21.6 vs 24.8
11.2 vs 11.3
18.2 vs 20.3*
24.2 vs 28*
20.4 vs 28.2*
15.9* vs 18.3
19.9 vs 24.2*
37.9 vs 42.3*
33 vs 40*
22 vs 24.3
30.2 vs 34.5*
85
40
132
73
Gleiter CH et al. Cardiovasc Drug Rev. 2004;22:263-84.
CHARM-Overall: Reduction in
new-onset diabetes
VBWG
Candesartan
n/N
Placebo
n/N
Hazard ratio
(95% CI)
P
163/2715 (6%)
202/2721 (7.4%)
0.78 (0.64–0.96)
0.02
n = new-onset diabetes
N = total patients
Pfeffer MA et al. Lancet. 2003;362:759-66.
VBWG
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. 2003;349:1893-906.
VBWG
VALIANT: Treatments show similar effect
on outcome
Death from any cause
Combined CV endpoint*
0.4
0.4
0.3
0.3
Probability
0.2
of event
0.2
0.1
0.1
0.0
0.0
0
6
12
18
24
30
36
0
Months
Valsartan
*CV death, reinfarction, or hospitalization for HF
6
12
18
24
30
36
Months
Valsartan/captopril
Captopril
Pfeffer MA et al. N Engl J Med. 2003;349:1893-906.
VBWG
VALIANT: Poorer 1-year outcomes in patients
with new-onset or previous diabetes
All-cause mortality
Adverse CV events
0.4
0.4
0.3
0.3
Previous DM
New DM
Probability 0.2
of event
Previous DM
0.2
No DM
New DM
0.1
No DM
0.1
0.0
0.0
0
3
6
9
12
0
3
9
12
Months
Months
P = 0.43
P < 0.001
P < 0.001
6
Previous vs new diabetes diagnosis
Previous vs no diabetes
New vs no diabetes diagnosis
P < 0.005
P < 0.001
P < 0.001
Aguilar D et al. Circulation. 2004;110:1572-8.
Clinical implications of CHARM
and VALIANT
VBWG
• In HF patients and in patients with acute MI and LV dysfunction,
evidence supports
– ARBs as alternative to ACEIs (in ACEI–intolerant 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. 2004;141:693-704.
McClellen MB et al. Ann Intern Med. 2005;142:386-7.
ACC/AHA. www.acc.org
VBWG
Benefit of ARB + ACE inhibitor in HF
HF hospitalization
ARB+
ACEI better
All-cause mortality
ARB+
ACEI better
ACEI
alone better
ACEI
alone better
CHARM
(HF)
VALIANT
(post MI + HF/LV dysfunction)
Val-HeFT
(HF)
0.6
0.8
1.0
1.2
1.4
0.6
0.8
1.0
1.2
1.4
Voors AA, van Veldhuisen DJ. Int J Cardiol. 2004;97:345-8.
VBWG
ARBs in LV dysfunction: Before/after
CHARM and VALIANT
ARBs superior to ACEI?
ARBs non-inferior to ACEI?
ARBs additive on top
of ACEI?
Combination ARB, ACEI,
and -blocker dangerous?
Before
CHARM, VALIANT
After
CHARM, VALIANT
No (ELITE II, OPTIMAAL)
No
? (ELITE II, OPTIMAAL)
Yes
? (Val-HeFT)
Yes, HF
No, post-MI
? (ELITE II, Val-HeFT)
No
Voors AA, van Veldhuisen DJ. Int J Cardiol. 2004;97:345-8.
Difference in target dosing among ARB trials
VBWG
Trial
Patients
Study drug
Outcome
CHARM Overall
HF
LVEF ≤40%
LVEF >40%
Candesartan 32 mg qd vs
Placebo
10%  mortality
13%  CV death
23%  HF hosp
ELITE II
HF
LVEF ≤40%
≥ 60 years
Losartan 50 mg qd vs
Captopril 50 mg tid
Similar  morbidity/mortality
OPTIMAAL
Post-MI + HF
Losartan 50 mg qd vs
Captopril 50 mg tid
Mortality trend favors captopril
No difference in morbidity
Val-HeFT
HF
Valsartan 160 mg bid vs
Placebo + conventional HF Rx
No  mortality
13.2%  morbidity/mortality
28%  HF hosp
VALIANT
Acute MI + HF/LV
dysfunction
Valsartan 160 mg bid or
Captopril 50 mg tid or
Valsartan 80 mg bid +
captopril 50 mg tid
Similar  mortality/morbidity
No added benefit with
ACEI+ARB
Pfeffer MA et al. Lancet. 2003;362:759-66.
Pitt B et al. Lancet. 2000;355:1582-7.
Dickstein K et al. Lancet. 2002;360:752-60.
Cohn JN et al. N Engl J Med. 2001;345:1667-75.
Pfeffer MA et al. N Engl J Med. 2003;349:1893-906.
Impact of RAAS modulation on mortality
in HF patients with renal insufficiency
VBWG
Minnesota Heart Survey
Post-discharge mortality
(mean follow-up 15 mo)
ACEI/ARB Rx at discharge
P = 0.17
7
6
80
64
5
Odds
ratio 4
(95%
CI) 3
63
60
P = 0.002
48
% 40
P = 0.04
P = 0.65
2
20
1
0
0
68
≥90
≥90
60–89
30–59
<30
60–89 30–59
GFR (mL/min)
<30
GFR (mL/min)
No ACEI/ARB at discharge
4926 patients hospitalized with HF
ACEI and/or ARB at discharge
Berger AK et al. Circulation. 2004;110 (suppl III):III-749.
VBWG
Summary
ACC/AHA stages of systolic HF
and treatment options
*In appropriate patients
VBWG
Jessup M, Brozena S. N Engl J Med. 2003;348:2007-18.