ARBs -CHF

1
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??a??s??? ?. ?a????? MD
2
Heart Failure Hospitalizations
The Number of Heart Failure Hospitalizations Is
Increasing in Both Men and Women
600,000
500,000
400,000
Annual Discharges
300,000
200,000
100,000
0
'79
'81
'83
'85
'87
'89
'91
'93
'95
'97
'99
Year
AHA. 2002 Heart and Stroke Statistical Update.
2001.
3
Evidence of improving survival from heart failure
in the general population
JACC Vol. 44, No. 12, 2004 2398-405
4
Recent trends in hospital admissions for heart
failure demonstrating recent plateau or decline
JACC Vol. 44, No. 12, 2004 2398-405
5
Renin-Angiotensin Aldosterone System
Non-ACE pathways(eg, chymase)

• Vasoconstriction
• Cell growth
• Na/H2O retention
• Sympathetic activation

Angiotensinogen
AT1
Renin
Angiotensin I
Angiotensin II
ACE
AT2
Aldosterone

• Vasodilation
• Antiproliferation(kinins)

Cough,angioedema Benefits?
Inactivefragments
? Bradykinin
6
Valsartan ACE-I in HF Valsartan Heart Failure
Trial (Val-HeFT)
5010 patients ?18 years EF lt40 NYHA IIIV
LVIDd gt2.9 cm/m2
Receiving standard therapy
ACE inhibitors (93), diuretics (86),digoxin
(67), ß-blockers (36)
Randomized to
Valsartan 40 mg bid titrated to 160 mg bid
Placebo
906 deaths (events recorded)
EJ ejection fraction LVIDd left ventricular
internal diastolic diameter. Cohn JN et al. Eur J
Heart Fail. 20002439-446.
7
Effect of Valsartan on Combined Mortality and
Morbidity End Point in Overall Population
Valsartan significantly reduces the combined
endpoint of mortality and morbidity and improves
clinical signs and symptoms in patients with
heart failure, when added to prescribed therapy.
All-cause mortality, sudden death with
resuscitation, hospitalization for worsening
heart failure, or therapy with IV inotropes or
vasodilators. Cohn JN et al. N Engl J Med.
20013451667-1675.
8
Val-HeFT Heart Failure-Related Hospitalizations
Valsartan (n 2511)
Placebo (n 2499)
Event-Free Probability
27.5 risk reduction
P lt0.001
3
6
9
12
15
18
21
24
27
0
30
Months
First hospitalization. Cohn JN et al. N Engl J
Med. 20013451667-1675.
9
Val-HeFT Hospitalization for Heart Failure
Adapted with permission from Carson P et al. J
Card Fail. 20039164-171.
10
Val-HeFT Combined Morbidity End Point
44 risk reduction
P lt0.0002
For morbidity 34 RR for mortality. Adapted
from Maggioni AP et al. J Am Coll Cardiol.
2002401414-1421.
11
Val-HeFT Change in Plasma Brain Natriuretic
Peptide Over Time
30
n 844
Placebo Baseline 177.6 pg/mL
n 1710
20
10
n 1890
? Plasma BNP(pg/mL)
0
P lt0.0001
P lt0.0001
P lt0.0001
-10
-20
n 823
-30
n 1633
n 1850
-40
24
0
4
12
Time (mo)
R et Mean SEM.Latini al. Circulation.
20021062454-2458.
12
Val-HeFT Neurohormones Change in Plasma NE
Over Time
(n 1894)
(n 1713)
(n 840)


40
Placebo Baseline 472 pg/mL
30
P 0.003
P 0.002
P 0.002
20

• Plasma
• NE (pg/mL)

10
(n 1855)
(n 1635)
0
(n 816)
-10
0
4
12
24
Time (mo)
NE norepinephrine.Mean SEM. Latini R et
al. Circulation. 20021062454-2458.
13
Val-HeFT Change From Baseline in Plasma
Aldosterone
30
Placebo
20
n 1749
n 1541
n 731
10

• Plasma Aldosterone (pg/mL)
• Least Squares Mean

0
-10
P lt0.0001
P lt0.0001
P lt0.0001
-20
Valsartan
n 727
-30
n 1459
-40
n 1718
4 months
12 months
24 months
Baseline
Anand I et al. AHA 75th Scientific Session.
2002A1763.
14
VALUE Design Elective titration to target BP
(lt140/90 mmHg)
V 160 mg HCTZ 25 mg "Free" add-on
V 160 mg HCTZ 25 mg
Valsartan-based regimen
V 160 mg HCTZ 12.5 mg
V 160 mg
V 80 mg
Rolloverfromprevious therapy(92)
A 5 mg
A 10 mg
A 10 mg HCTZ 12.5 mg
Amlodipine-based regimen
A 10 mg HCTZ 25 mg
A 10 mg HCTZ 25 mg "Free" add-on
Month 0.5 0 1 2 3 4 6 72
Screening
End of treatment adjustment period
Randomisation
Patient visits every 6 months for months 672.
Julius S et al. Lancet. June 2004363.
15
VALUE Primary Composite Cardiac Endpoint
14 12 10 8 6 4 2 0
Valsartan-based regimen
Amlodipine-based regimen
Proportion of Patients With First Event ()
HR 1.03 95 CI 0.941.14 P 0.49
0 6 12 18 24 30 36 42 48 54 60 66
Time (months)
Number at risk
7649
7459
7407
7250
7085
6732
6906
6536
5911
3765
1474
6349
Valsartan
Amlodipine
7596
7469
7424
7267
7117
6772
6955
6576
5959
3725
1474
6391
Julius S et al. Lancet. June 2004363.
16
VALUE Outcome and SBP Differences at Specific
Time Periods Primary Endpoint
Time Interval
PRIMARY ENDPOINT Odds Ratios and 95 CIs
SBP
D
(months)
mmHg
Overall study
2.2
3.8
03
36
2.3
612
2.0
1224
1.8
2436
1.6
3648
1.4
Study end
1.7
1.0
2.0
0.5
4.0
Favours valsartan
Favours amlodipine
Julius S et al. Lancet. June 2004363.
17
VALUE Heart Failure
Hospitalisation for HF or death from HF
9 8 7 6 5 4 3 2 1 0
Valsartan-based regimen
Amlodipine-based regimen
Proportion of Patients With First Event ()
HR 0.89 95 CI 0.77-1.03 P 0.12
0 6 12 18 24 30 36 42 48 54 60 66
Time (months)
Number at risk
Valsartan
7649
7485
7444
7312
7169
6852
7012
6671
6072
3860
1513
6498
Amlodipine
7596
7486
7444
7312
7176
6874
7033
6702
6100
3823
1511
6534
Julius S et al. Lancet. June 2004363.
18
VALUE Outcome and SBP Differencesat Specific
Time Periods Heart Failure
Time interval
Heart Failure Odds Ratios and 95 CIs
? SBP
(months)
(mmHg)
Overall study
2.2
3.8
03
2.3
36
2.0
612
1.8
1224
1.6
2436
1.4
3648
Study end
1.7
1.0
2.0
0.5
0.25
4.0
Favours amlodipine
Favours valsartan
Heart Failure Hospitalisation for HF or death
from HF.
Julius S et al. Lancet. June 2004363.
19
VALUE Analysis of Results Based on BP Control
at 6 Months
Patients Treated With Valsartan
Patients Treated With Amlodipine
Odds Ratio
Odds Ratio
Fatal/Non-fatal cardiac events
0.76 (0.660.88)


0.73 (0.630.85)
Fatal/Non-fatal stroke
0.60 (0.480.74)
0.50 (0.390.64)


0.79 (0.690.92)


0.79 (0.690.91)
All-cause death
0.83 (0.661.03)
0.91 (0.711.17)
Myocardial infarction
Heart failure hospitalisations
0.62 (0.500.77)


0.64 (0.520.79)
0.4
0.6
0.8
1.0
1.2
0.4
0.6
0.8
1.0
1.2
Controlled patients (n 5253)
Non-controlled patients (n 2396)
Controlled patients (n 5502)
Non-controlled patients (n 2094)
Hazard Ratio 95 CI
Hazard Ratio 95 CI
SBP lt 140 mmHg at 6 months.
P lt 0.01.
Weber MA et al. Lancet. 2004363204749.
20
VALUE Analysis of Results Based on BP Control
at 6 Months
Pooled Treatment Groups
Odds Ratio

Fatal/Non-fatal cardiac events
0.75 (0.670.83)

Fatal/Non-fatal stroke
0.55 (0.460.64)

All-cause death
0.79 (0.710.88)
Myocardial infarction
0.86 (0.731.01)

Heart failure hospitalisations
0.64 (0.550.74)
0.4
0.6
0.8
1.0
1.2
1.4
Controlled patients (n 10755)
Non-controlled patients (n 4490)
Hazard Ratio 95 CI
SBP lt 140 mmHg at 6 months.
P lt 0.01.
Weber MA et al. Lancet. 2004363204749.
21
VALUE Major Study Endpoints in 5006 Patient
Pairs (N 10,012) on Valsartan- or
Amlodipine-Based Therapies Using Serial Median
Matching
Hazard Ratio (95 CI)
P
Composite cardiac events
0.90 (0.791.03)
0.111
Stroke
1.02 (0.811.28)
0.899
Death
0.96 (0.841.10)
0.566
Myocardial infarction
0.97 (0.801.19)
0.791
Heart failure
0.81 (0.660.99)
0.040
0.6
0.8
1.0
1.2
1.4
Favours valsartan
Favours amlodipine
P lt 0.05.
Weber MA et al. Lancet. 2004363204749.
22
Acute MI (0.510 days)SAVE, AIRE or TRACE
eligible(either clinical/radiologic signs of HF
or LV systolic dysfunction)
double-blind active-controlled
Captopril 50 mg tid (n 4909)
Valsartan 160 mg bid (n 4909)
Captopril 50 mg tid Valsartan 80 mg bid (n
4885)
median duration 24.7 monthsevent-driven
Primary Endpoint All-Cause Mortality Secondary
Endpoints CV Death, MI, or HF Other
Endpoints Safety and Tolerability
23
Mortality by Treatment
0.3
0.25
0.2
0.15
Probability of Event
0.1
0.05
Valsartan vs. Captopril HR 1.00 P 0.982
Valsartan Captopril vs. Captopril HR 0.98 P
0.726
0
Months
0
6
12
18
24
30
36
Captopril 4909 4428 4241 4018 2635 1432 364

Valsartan 4909 4464 4272 4007 2648 1437 357
Valsartan Cap 4885 4414 4265 3994 2648 1435 382
Pfeffer, McMurray, Velazquez, et al. N Engl J Med
2003349
24
All-Cause MortalityNon-Inferiority Analyses
Hazard Ratio(97.5 CI)
P-value(noninferiority)
noninferiority margin
0.8
1
1.2
1.13
Favors Valsartan
Favors Captopril
25
Mortality in SAVE,TRACE, AIRE, and VALIANT
Hazard Ratio for Mortality
Valsartan preserves 99.6 of mortality benefit of
captopril.
FavorsActive Drug
FavorsPlacebo
26
CV Death, MI, or HFby Treatment
0.4
0.3
Probability of Event
0.2
0.1
Valsartan vs. Captopril HR 0.96 P 0.198
Valsartan Captopril vs. Captopril HR 0.97 P
0.369

0
Months
0
6
12
18
24
30
36
Pfeffer, McMurray, Velazquez, et al. N Engl J Med
2003349
27
CardiovascularMortality and Morbidity
Hazard Ratio(97.5 CI)
P-value(noninferiority)
noninferiority margin
0.8
1
1.2
1.13
Favors Valsartan
Favors Captopril
28
Hazard Ratios (95 CI)for CV Death, MI, or HF
of Pts.
P-Value(interaction)
of Pts.
P-Value(interaction)
Median lt 65Age ³ 65 Sex Male Female Prior
MI No Yes DM No Yes SBP median gt
median Serum medianCr gt median Killip
IClass II III IV
46185200 67383080 70882730 75642254 56324182
49704837 271847471687619
46755119 67683026 70852709 75282266 56424149
49084878 280546751655618
0.96 0.55 0.93 0.12 0.71 0.67 0.84
1.00 0.47 0.26 0.85 0.68 0.92 0.11
29106882
Beta- NoBlocker Yes
29076911
0.48
0.56
0.5
1
2
0.5
1
2
Favors Valsartan
Favors Captopril
29
Hazard Ratios (95 CI)for CV Death, MI, or HF
Favors Captopril
Favors Valsartan
P-Value (interaction)
Valsartan vs. Captopril No Beta-Blocker (n
2907) Beta-Blocker (n 6911)
0.48
Combination vs. Captopril No Beta-Blocker (n
2910) Beta-Blocker (n 6882)
0.56
1
2
0.5
Favors Captopril
Favors Combination
30
CHARM Programme
3 component trials comparing candesartan to
placebo
CHARM Added
CHARMPreserved
CHARMAlternative
n3025 LVEF gt40 ACE inhibitor treated/not
treated
n2028 LVEF 40ACE inhibitor intolerant
n2548 LVEF 40ACE inhibitor treated
Primary outcome CV death or CHF hosp
31
CHARM-Alternative Primary outcome CV death or
CHF hospitalisation

50
406 (40.0)
Placebo
40
334 (33.0)
30
Candesartan
20
10
HR 0.77 (95 CI 0.67-0.89), p0.0004Adjusted HR
0.70, plt0.0001
0
0
1
2
3
years
3.5
Number at risk Candesartan 1013
929 831 434
122 Placebo 1015 887
798 427 126
32
CHARM-Alternative Primary outcome CV death or
CHF hospitalisation

50
406 (40.0)
Placebo
40
334 (33.0)
30
Candesartan
20
10
HR 0.77 (95 CI 0.67-0.89), p0.0004Adjusted HR
0.70, plt0.0001
0
0
1
2
3
years
3.5
Number at risk Candesartan 1013 929 831 434 122 P
lacebo 1015 887 798 427 126
33
CHARM-Alternative Secondary outcomes
p-value
Candesartan
Placebo
0.85
CV death 219 252 CHF hosp. 207 286 CV death,
CHF hosp, 353 420 MI CV death, CHF
hosp, 369 432 MI, stroke CV death, CHF
hosp, 396 456 MI, stroke, revasc
0.072
0.68
lt0.0001
0.78
0.0007
0.80
0.001
0.81
0.002
0.6
0.8
1.0
1.2
1.4
candesartan better
Hazard ratio
placebo better
34
CHARM-Alternative Investigator reported CHF
hospitalisations
Placebo
Candesartan
Proportion of patients ()
Number of episodes
p0.0001
plt0.0001
Hospitalisations
Patients hospitalised
35
CHARM Programme
3 component trials comparing Candesartan to
placebo
CHARM Added
CHARMPreserved
CHARMAlternative
n3025 LVEF gt40ACE inhibitor treated/not
treated
n2028 LVEF 40 ACE inhibitor intolerant
n2548 LVEF 40ACE inhibitor treated
Primary outcome CV death or CHF hosp
36
CHARM-Added Primary outcomeCV death or CHF
hospitalisation

50
538 (42.3)
Placebo
40
483 (37.9)
30
Candesartan
20
10
HR 0.85 (95 CI 0.75-0.96), p0.011Adjusted HR
0.85, p0.010
0
0
1
2
3
years
3.5
Number at risk Candesartan 1276 1176 1063
948 457 Placebo 1272 1136 1013
906 422
37
CHARM-Added Primary outcomeCV death or CHF
hospitalisation

50
538 (42.3)
Placebo
40
483 (37.9)
30
Candesartan
20
10
HR 0.85 (95 CI 0.75-0.96), p0.011Adjusted HR
0.85, p0.010
0
0
1
2
3
years
3.5
Number at risk Candesartan 1276 1176 1063 948 457
Placebo 1272 1136 1013 906 422
38
CHARM-Added Secondary outcomes
p-value
Candesartan
Placebo
0.84
CV death 302 347 CHF hosp. 309 356 CV death,
CHF hosp, 495 550 MI CV death,CHF
hosp, 512 559 MI, stroke CV death,CHF
hosp, 548 596 MI, stroke, revasc
0.029
0.83
0.014
0.85
0.010
0.87
0.020
0.87
0.015
0.6
0.8
1.0
1.2
1.4
candesartan better
Hazard ratio
placebo better
39
CHARM-AddedPrespecified subgroups, CV death or
CHF hosp.
p-value for treatment interaction
Placebo
Candesartan
Beta- Yes 223/702 274/711blocker No 260/574 264/
561 Recom. Yes 232/643 275/648dose
of No 251/633 263/624ACE inhib. All
patients 483/1276 538/1272
0.14
0.26
0.6
0.8
1.0
1.2
1.4
candesartan better
Hazard ratio
placebo better
40
CHARM-Added Investigator reported CHF
hospitalisations
Placebo
Candesartan
Proportion of patients ()
Number of episodes
p0.008
p0.002
Hospitalisations
Patients hospitalised
41
(No Transcript)
42
Diastolic Heart Failure Effects of Age on
Prevalence and Prognosis

• Age, y
• lt50 50-70 gt70

Prevalence 15 33 50 Mortality
15 33 50 Morbidity 25 50 50
43
Patients with Preserved Versus Depressed EF
Smith et al. J Am Coll Cardiol 2003
44
Outcomes in Hf Patients with Preserved EF
Smith GL et al. J Am Coll Cardiol 2003
45
Definition of Diastolic Dysfunction and HF

• Diastolic HF is a clinical syndrome
  characterized by the symptoms and signs of HF, a
  preserved EF and abnormal diastolic function.
• Diastolic dysfunction occurs when the time period
  during which the myocardium loses its ability to
  generate force and shorten and returns to an
  unstressed length and force, is prolonged, slowed
  or incomplete.
• Systolic and diastolic HF occurs when patients
  have a modest decrease in EF and a modest
  increase in end-diastolic volume but a marked
  increase in end-diastolic pressure and a
  diastolic pressure-volume relationship that
  reflects decreased chamber compliance.

Zile MR et al. Circulation 2002
46
CHARM Programme
3 component trials comparing candesartan to
placebo
CHARM Added
CHARMPreserved
CHARMAlternative
n3025 LVEF gt40ACE inhibitor treated/not
treated
n2028 LVEF 40 ACE inhibitor intolerant
n2548 LVEF 40ACE inhibitor treated
Primary outcome CV death or CHF hosp
47
CHARM-Preserved Primary outcome CV death or CHF
hospitalisation

30
366 (24.3)
Placebo
25
333 (22.0)
20
Candesartan
15
10
HR 0.89 (95 CI 0.77-1.03), p0.118Adjusted HR
0.86, p0.051
5
0
0
1
2
3
years
3.5
Number at risk Candesartan 1514 1458 1377 833 182
Placebo 1509 1441 1359 824 195
48
CHARM-Preserved Primary and secondary outcomes
Covariate adjustedp-value
p-value
Candesartan
Placebo
0.89
0.118
0.051
CV death, CHF hosp. 333 366 - CV death 170 170
- CHF hosp. 241 276 CV death, CHF
hosp, 365 399 MI CV death,CHF hosp, 388 429
MI, stroke CV death,CHF hosp, 460 497 MI,
stroke, revasc
0.99
0.918
0.635
0.85
0.072
0.047
0.90
0.126
0.051
0.88
0.078
0.037
0.91
0.123
0.13
0.8
1.0
1.2
candesartan better
Hazard ratio
placebo better
49
CHARM-Preserved Primary outcome CV death or CHF
hospitalisation

30
366 (24.3)
Placebo
25
333 (22.0)
20
Candesartan
15
10
HR 0.89 (95 CI 0.77-1.03), p0.118Adjusted HR
0.86, p0.051
5
0
0
1
2
3
years
3.5
Number at risk Candesartan 1514 1458 1377 833 182
Placebo 1509 1441 1359 824 195
50
CHARM-Preserved Primary and secondary outcomes
Covariate adjustedp-value
p-value
Candesartan
Placebo
0.89
0.118
0.051
CV death, CHF hosp. 333 366 - CV death 170 170
- CHF hosp. 241 276 CV death, CHF
hosp, 365 399 MI CV death,CHF hosp, 388 429
MI, stroke CV death,CHF hosp, 460 497 MI,
stroke, revasc
0.99
0.918
0.635
0.85
0.072
0.047
0.90
0.126
0.051
0.88
0.078
0.037
0.91
0.123
0.13
0.8
1.0
1.2
candesartan better
Hazard ratio
placebo better
51
CHARM-Preserved Investigator reported CHF
hospitalisations
Placebo
Candesartan
Proportion of patients ()
Number of episodes
p0.014
p0.017
Hospitalisations
Patients hospitalised