Background

1
Background

• James B. Young, MD
• Chair, Division of MedicineCleveland Clinic
  Foundation

2
Heart FailureAn Increasing Public Health Burden
30

• Affects 5 million US residents(2.2 of the
  population)
• Lifetime risk 20 for men and women
• 550,000 new cases annually
• Causes or contributes to 300,000deaths annually
• 50 5-year mortality
• No. 1 cause of hospitalizations in the elderly
• 1 million hospital discharges annually
  (associated with poor prognosis)

3
FraminghamHF Survival by Gender
CB-3
Men
1.0
1950-1969 1970-1979 1980-1989 1990-1999
0.8
0.6
Probabilityof survival
0.4
0.2
0.0
0
2
4
6
8
10
Yr
Women
1.0
1950-1969 1970-1979 1980-1989 1990-1999
0.8
0.6
Probabilityof survival
0.4
0.2
0.0
0
2
4
6
8
10
Yr
Levy, et al. N Engl J Med 20023471397.
4
FDA Question 1.4

• Are ACE inhibitors and ARBs sufficiently
  different that CHARM-Added can support use of
  candesartan with ACE inhibitors?

5
RAAS In Heart Failure
CB-5
Renin-Angiotensin System
Angiotensinogen

• Non-Renin
• Tonin
• Cathepsin

Renin inhibitors
Renin
Angiotensin I
Bradykinin
BKR
ACE/ BPF

• Non-ACE
• Chymase

ACE inhibitors
NO?
Angiotensin II

• Vasodilation
• ? Ischemia
• ? Platelet agg
• ? inotrope

Inactive Peptides
Cross talk

• AT II
• Vasodilation
• Anti proliferation
• ? Kinins
• ? NO

• AT I
• Vasoconstriction
• Cell growth
• Na/H2O retention
• SNS activation

RAAS MODULATORS Spironolactone
Eplerenone Beta blockers
Enzymatic activity Enzymatic blockade Product/rece
ptor stimulation
6
RAAS In Heart Failure ACE Inhibition
CB-6
Renin-Angiotensin System
Angiotensinogen

• Non-Renin
• Tonin
• Cathepsin

Renin inhibitors
Renin
Angiotensin I
Bradykinin
BKR
ACE/ BPF

• Non-ACE
• Chymase

ACE inhibitors
NO?
Angiotensin II

• Vasodilation
• ? Ischemia
• ? Platelet agg
• ? inotrope

Inactive Peptides
Cross talk

• AT II
• Vasodilation
• Anti proliferation
• ? Kinins
• ? NO

• AT I
• Vasoconstriction
• Cell growth
• Na/H2O retention
• SNS activation

RAAS MODULATORS Spironolactone
Eplerenone Beta blockers
Enzymatic activity Enzymatic blockade Product/rece
ptor stimulation
7
RAAS In Heart Failure ARBs
CB-7
Renin-Angiotensin System
Angiotensinogen

• Non-Renin
• Tonin
• Cathepsin

Renin inhibitors
Renin
Angiotensin I
Bradykinin
BKR
ACE/ BPF

• Non-ACE
• Chymase

ACE inhibitors
NO?
Angiotensin II

• Vasodilation
• ? Ischemia
• ? Platelet agg
• ? inotrope

Inactive Peptides
Cross talk

• AT II
• Vasodilation
• Anti proliferation
• ? Kinins
• ? NO

• AT I
• Vasoconstriction
• Cell growth
• Na/H2O retention
• SNS activation

RAAS MODULATORS Spironolactone
Eplerenone Beta blockers
Enzymatic activity Enzymatic blockade Product/rece
ptor stimulation
8
RAAS In Heart Failure ACE Inhibition/ARB
CB-8
Renin-Angiotensin System
Angiotensinogen

• Non-Renin
• Tonin
• Cathepsin

Renin inhibitors
Renin
Angiotensin I
Bradykinin
BKR
ACE/ BPF

• Non-ACE
• Chymase

ACE inhibitors
NO?
Angiotensin II

• Vasodilation
• ? Ischemia
• ? Platelet agg
• ? inotrope

Inactive Peptides
Cross talk

• AT II
• Vasodilation
• Anti proliferation
• ? Kinins
• ? NO

• AT I
• Vasoconstriction
• Cell growth
• Na/H2O retention
• SNS activation

RAAS MODULATORS Spironolactone
Eplerenone Beta blockers
Enzymatic activity Enzymatic blockade Product/rece
ptor stimulation
9
Summary of ARB ACEi in Animal ModelsRecent
Studies

• ARB and ACEi was more effective than either
  monotherapy alone on the following models
• Heart failure in dogs improved function and
  remodeling
• Nakamura et al, Cardiovasc Res 2003
• Koji et al, Cardiovasc Pharmacol 2003
• Funabiki et al, Am J Heart Circ Physiol 2004
• Heart failure in rats decreased remodeling
• Yu et al, J Am Coll Cardiol 2001
• Kim et al, Circulation 2001
• Obese Zucker rats decreased renal damage and LVH
  
• Eduardo et al, Kidney International 2004
• Spontaneously hypertensive rats decreased LVH,
  preserved renal function
• Raasch et al, J Hypertension 2004

10
Long-Term Effect of Enalapril (20 mg) on Plasma
ACE and Angiotensin II
46
100
80
60
Plasma ACE,nmol/mL/min
40

20







0
30
20
Plasma ANG II, pg/mL

10
0
4 h
24 h
1
2
3
4
5
6
Placebo
Months
Hospital
p lt 0.001 vs placebo. Biollaz J, et al. J
Cardiovasc Pharmacol 19824966-972.
11
Bradykinin Antagonism Attenuates ACE Inhibitor
But Not ARB Effects
n 14 patients Enalapril 10 mg bid Losartan
50 mg bid
Cruden LM, et al. Arterioscler Thromb Vasc Biol
2004241043-1048.
12
ACEi ARB Incremental Benefit Renal Studies
13
COOPERATE Trial
42
Nakao N et al. Lancet 2003361117-124
14
Proportion of Patients Reaching
EndpointCOOPERATE Trial
42
30
Combination
Losartan
25
Trandolapril
20
Proportion reaching endpoint, (renal failure or
CrC2)
15
10
5
p 0.018
0
0
6
12
18
24
30
36
Months after randomization
At risk, n Losartan 89 88 84 79 65 59 47 Trandolap
ril 86 85 83 75 72 63 58 Combination 88 87 86 83 7
6 73 67
Nakao N et al. Lancet 2003361117-124
15
Change From Baseline in SBP, PCWP, and PADP at
0-Hr Trough After 4 Wk of TherapyVal-HeFT Pilot
Study
SBP
PCWP
PADP
2
0
2
4
Change in mm Hg
6
p 0.013
8
10
p 0.013
12
Baruch L, et al. Circulation 1999992658-2664.
16
Change in Brain Natriuretic Peptide(BNP) From
BaselineRESOLVD Pilot Study
10
Candesartan 16 mg
Picogram/ml
Candesartan 8 mg enalapril 20 mg
0
Enalapril 20 mg
-10


17 wk
43 wk
p lt 0.01 Adapted from McKelvie R, et al.
Circulation 19991001056-1064.
17
Therapeutic Effects on End Systolic and End
Diastolic VolumesRESOLVD Pilot Study
Candesartan 4 - 16 mg Enalapril 20 mg Combo
(Candesartan Enalapril)
n 768
Diastolic(Change in EDV)
Systolic (Change in ESV)
Volume, mL
p lt 0.01
p lt 0.05
0 17 43 Time, wk
0 17 43 Time, wk
McKelvie RS, et al. Circulation 19991001056.
18
Benefits of Adding an ARB to an ACE Inhibitor
Peak oxygen uptake
NYHA functional class
4.0
17
16
3.5
15
ml/kg/min
3.0
p lt 0.02
14
p lt 0.01
2.5
13
2.0
12
Before Rx
Month 3
Month 6
Before Rx
Month 3
Month 6
ACEi Losartan 50 mg/d
ACEi Placebo
Hamroff G, et al. Circulation 199999990-992.
19
Setting the Stage for CHARM

• It is imperative that new strategies to reduce
  the morbidity and mortality of HF be developed
• Attenuating adverse effects of RAAS activation
  with ACE inhibition and ARB is well established
• The concept of ACE inhibitor/ARB combination in
  CHF is supported by
• Preclinical basic science information
• Clinical outcomes data in diabetics and CRI
  patients
• Hemodynamic observations in CHF
• Neurohormonal modulation in CHF
• Observations on cardiac remodeling in CHF
• Improved symptomatic and exercise profiles in CHF
• CHARM Added are clinical outcomes improved?