cb-1 background james b. young, md chair, division of medicine cleveland clinic foundation

CB-1

Background

James B. Young, MD

Chair, Division of MedicineCleveland Clinic Foundation

CB-2

Heart FailureAn Increasing Public Health Burden

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 300,000

deaths annually 50% 5-year mortality No. 1 cause of hospitalizations in the elderly ~1 million hospital discharges annually

(associated with poor prognosis)

30

Framingham—HF Survival by Gender

1950-19691970-19791980-19891990-1999

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10

1950-19691970-19791980-19891990-1999

Women

Men

Probabilityof survival

Probabilityof survival

Yr

Yr

Levy, et al. N Engl J Med 2002;347:1397.

CB-3

CB-4

FDA Question 1.4

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

Renin-Angiotensin SystemRenin-Angiotensin System

Renin inhibitorsRenin inhibitors

AngiotensinogenAngiotensinogen

ReninRenin

Angiotensin Angiotensin II

Non-ReninNon-Renin•ToninTonin•CathepsinCathepsin

ACE inhibitorsACE inhibitorsACE/ACE/BPFBPF

Angiotensin Angiotensin IIII

Non-ACENon-ACE•ChymaseChymase

AT IIAT II• VasodilationVasodilation• Anti proliferationAnti proliferation KininsKinins NONO

AT IAT I• VasoconstrictionVasoconstriction• Cell growthCell growth• NaNa++/H/H22O retentionO retention• SNS activationSNS activation

Cross talkCross talk

RAAS MODULATORSRAAS MODULATORS:: SpironolactoneSpironolactone EplerenoneEplerenone Beta blockersBeta blockers

BradykininBradykinin

Inactive Inactive PeptidesPeptides

BKRBKR

• VasodilationVasodilation IschemiaIschemia Platelet aggPlatelet agg inotropeinotrope

NONO

Enzymatic activityEnzymatic activityEnzymatic blockadeEnzymatic blockadeProduct/receptor stimulationProduct/receptor stimulation

RAAS In Heart FailureCB-5




ReninRenin












BKRBKR


NONO


RAAS In Heart Failure: ACE InhibitionCB-6




ReninRenin












BKRBKR


NONO


RAAS In Heart Failure: ARBsCB-7




ReninRenin












BKRBKR


NONO


RAAS In Heart Failure: ACE Inhibition/ARBCB-8

CB-9

Summary of ARB + ACEi in Animal Models—Recent 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

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*

Long-Term Effect of Enalapril (20 mg) on Plasma ACE and Angiotensin II

100

60

20

80

40

0*

* * * * * *

30

20

10 *

04 h 24 h 1 2 3 4 5 6

MonthsPlacebo

Hospital

Pla

sma

AN

G II

,p

g/m

LP

lasm

a A

CE

,n

mo

l/mL

/min

* p < 0.001 vs placebo.Biollaz J, et al. J Cardiovasc Pharmacol 1982;4:966-972.

46

CB-11

Bradykinin Antagonism Attenuates ACE Inhibitor But Not ARB Effects

Cruden LM, et al. Arterioscler Thromb Vasc Biol 2004;24:1043-1048.

n = 14 patientsEnalapril = 10 mg bidLosartan = 50 mg bid

CB-12

ACEi + ARB Incremental Benefit Renal Studies

Patients Design ACE Inhibitor ARB ACEI +ARB vs. ACEI alone p value

Jacobsen et alJASN2003

N = 18Type 1 DM

DBX-Over8 wks

Benazepril 20 mg Valsartan80 mg

43% greater reduction in albuminuria

6/7 mmHg greater reduction in 24-h BP

< 0.01

0.06/< 0.001

Rossing et alDiabetes Care2003

N = 20 Type 2 DM

DB X-Over8 wks

Enalapril/Lisinopril 40 mgorCaptopril 150 mg

Candesartan 16 mg

28% greater reduction in albuminuria

3/2 mmHg greater reduction in24-h BP

< 0.001

NS

Jacobsen et alKI2003

N = 24 Type 1 DM

DB X-Over8 wks

Enalapril 40 mg Irbesartan 300 mg

25% greater reduction in albuminuria8/4 mmHg greater reduction in

24-h BP64% greater reduction in renin

< 0.001

< 0.031

< 0.05

CB-13

COOPERATE Trial

42

Study population 263 pts with nondiabetic kidney disease

Study design Run-in to determine maximum antiproteinuric ACEi dose (trandolapril 3 mg) then randomization to trandolapril3 mg, losartan 100 mg, or both

Primary outcome Doubling of serum creatinine or ESRD

Nakao N et al. Lancet 2003;361:117-124

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Proportion of Patients Reaching EndpointCOOPERATE Trial

Nakao N et al. Lancet 2003;361:117-124

0 6 12 18 24 30 36

30

25

20

15

10

5

0Pro

po

rtio

n r

ea

ch

ing

en

dp

oin

t, %

(re

na

l fa

ilu

re o

r C

rC×

2)

Combination

Months after randomization

LosartanTrandolapril

42

At risk, n

Losartan 89 88 84 79 65 59 47Trandolapril 86 85 83 75 72 63 58Combination 88 87 86 83 76 73 67

p = 0.018

CB-15Change From Baseline in SBP, PCWP, and PADP at 0-Hr Trough After 4 Wk of TherapyVal-HeFT Pilot Study

Placebo + Lisinopril 10/20 mg

Valsartan 80 mg BID + Lisinopril 10/20 mg (V80)

Valsartan 160 mg BID + Lisinopril 10/20 mg (V160)

SBP PCWP PADP

p = 0.013

p = 0.013

2

0

–2

–4

–6

–8

–10

–12

Ch

ang

e in

mm

Hg

Baruch L, et al. Circulation 1999;99:2658-2664.

CB-16Change in Brain Natriuretic Peptide(BNP) From BaselineRESOLVD Pilot Study

-10

0

10

Pic

og

ram

/ml

Candesartan 16 mg

Candesartan 8 mg+ enalapril 20 mg

Enalapril 20 mg

**pp < 0.01 < 0.01Adapted from McKelvie R, et al. Adapted from McKelvie R, et al. Circulation Circulation 1999;100:1056-1064.1999;100:1056-1064.

17 wk 43 wk* *

CB-17

-5

5

15

25

35

45

Therapeutic Effects on End Systolic and End Diastolic VolumesRESOLVD Pilot Study

-5

5

15

25

35

45

0 17 43Time, wk

0 1743

Time, wk

Vo

lum

e, m

L

McKelvie RS, et al. Circulation 1999;100:1056.

Diastolic(Change in EDV)

Systolic (Change in ESV)

n = 768Candesartan 4 - 16 mg Enalapril 20 mg Combo (Candesartan + Enalapril)

p < 0.01

p < 0.05

CB-18

Benefits of Adding an ARB to an ACE Inhibitor

Hamroff G, et al. Circulation 1999;99:990-992.

Before Rx Month 3 Month 612

13

14

15

16

17

Peak oxygen uptake

ACEi + Placebo

ACEi + Losartan 50 mg/d

p < 0.02

Before Rx Month 3 Month 62.0

2.5

3.0

3.5

4.0

NYHA functional class

p < 0.01ml/k

g/m

in

CB-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?

cb-1 background james b. young, md chair, division of medicine cleveland clinic foundation

Documents

heart failurean

remodelingnakamura et

kim et

koji et

funabiki et

j heart circ physiol

decreased remodelingyu

lvh eduardo et