1. CB-1 Background James B. Young, MD Chair, Division of Medicine Cleveland Clinic Foundation

2. CB-2 Heart Failure An 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

3. Framingham— HF Survival by Gender 1950-1969 1970-1979 1980-1989 1990-1999 0.0 0.2 0.4 0.6 0.8 1.0 0246810 0.0 0.2 0.4 0.6 0.8 1.0 0246810 1950-1969 1970-1979 1980-1989 1990-1999 Women Men Probability of survival Yr Levy, et al. N Engl J Med 2002;347:1397. CB-3

4. CB-4 FDA Question 1.4 Are ACE inhibitors and ARBs sufficiently different that CHARM-Added can support use of candesartan with ACE inhibitors?

5. Renin-Angiotensin System Renin inhibitors Angiotensinogen Renin Angiotensin I Non-Renin ToninTonin CathepsinCathepsin ACE inhibitors ACE/BPF Angiotensin II Non-ACE ChymaseChymase AT II VasodilationVasodilation Anti proliferationAnti proliferation  Kinins  Kinins  NO  NO AT I VasoconstrictionVasoconstriction Cell growthCell growth Na + /H 2 O retentionNa + /H 2 O retention SNS activationSNS activation Cross talk RAAS MODULATORS: Spironolactone Spironolactone Eplerenone Eplerenone Beta blockers Beta blockers Bradykinin InactivePeptides BKR VasodilationVasodilation  Ischemia  Ischemia  Platelet agg  Platelet agg  inotrope  inotrope NO  Enzymatic activity Enzymatic blockade Product/receptor stimulation RAAS In Heart Failure CB-5

6. Renin-Angiotensin System Renin inhibitors Angiotensinogen Renin Angiotensin I Non-Renin ToninTonin CathepsinCathepsin ACE inhibitors ACE/BPF Angiotensin II Non-ACE ChymaseChymase AT II VasodilationVasodilation Anti proliferationAnti proliferation  Kinins  Kinins  NO  NO AT I VasoconstrictionVasoconstriction Cell growthCell growth Na + /H 2 O retentionNa + /H 2 O retention SNS activationSNS activation Cross talk RAAS MODULATORS: Spironolactone Spironolactone Eplerenone Eplerenone Beta blockers Beta blockers Bradykinin InactivePeptides BKR VasodilationVasodilation  Ischemia  Ischemia  Platelet agg  Platelet agg  inotrope  inotrope NO  Enzymatic activity Enzymatic blockade Product/receptor stimulation RAAS In Heart Failure: ACE Inhibition CB-6

7. Renin-Angiotensin System Renin inhibitors Angiotensinogen Renin Angiotensin I Non-Renin ToninTonin CathepsinCathepsin ACE inhibitors ACE/BPF Angiotensin II Non-ACE ChymaseChymase AT II VasodilationVasodilation Anti proliferationAnti proliferation  Kinins  Kinins  NO  NO AT I VasoconstrictionVasoconstriction Cell growthCell growth Na + /H 2 O retentionNa + /H 2 O retention SNS activationSNS activation Cross talk RAAS MODULATORS: Spironolactone Spironolactone Eplerenone Eplerenone Beta blockers Beta blockers Bradykinin InactivePeptides BKR VasodilationVasodilation  Ischemia  Ischemia  Platelet agg  Platelet agg  inotrope  inotrope NO  Enzymatic activity Enzymatic blockade Product/receptor stimulation RAAS In Heart Failure: ARBs CB-7

8. Renin-Angiotensin System Renin inhibitors Angiotensinogen Renin Angiotensin I Non-Renin ToninTonin CathepsinCathepsin ACE inhibitors ACE/BPF Angiotensin II Non-ACE ChymaseChymase AT II VasodilationVasodilation Anti proliferationAnti proliferation  Kinins  Kinins  NO  NO AT I VasoconstrictionVasoconstriction Cell growthCell growth Na + /H 2 O retentionNa + /H 2 O retention SNS activationSNS activation Cross talk RAAS MODULATORS: Spironolactone Spironolactone Eplerenone Eplerenone Beta blockers Beta blockers Bradykinin InactivePeptides BKR VasodilationVasodilation  Ischemia  Ischemia  Platelet agg  Platelet agg  inotrope  inotrope NO  Enzymatic activity Enzymatic blockade Product/receptor stimulation RAAS In Heart Failure: ACE Inhibition/ARB CB-8

9. 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

10. CB-10 * Long-Term Effect of Enalapril (20 mg) on Plasma ACE and Angiotensin II 100 60 20 80 40 0 * * * * * * * 30 20 10 * 0 4 h24 h123456 Months Placebo Hospital Plasma ANG II, pg/mL Plasma ACE, nmol/mL/min * p < 0.001 vs placebo. Biollaz J, et al. J Cardiovasc Pharmacol 1982;4:966-972. 46

11. 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 patients Enalapril = 10 mg bid Losartan = 50 mg bid

12. CB-12 ACEi + ARB Incremental Benefit Renal Studies PatientsDesignACE InhibitorARBACEI +ARB vs. ACEI alone p value Jacobsen et al JASN 2003 N = 18 Type 1 DM DB X-Over 8 wks Benazepril 20 mgValsartan 80 mg 43% greater reduction in albuminuria 6/7 mmHg greater reduction in 24-h BP < 0.01 0.06/ < 0.001 Rossing et al Diabetes Care 2003 N = 20 Type 2 DM DB X-Over 8 wks Enalapril/ Lisinopril 40 mg or Captopril 150 mg Candesartan 16 mg 28% greater reduction in albuminuria 3/2 mmHg greater reduction in 24-h BP < 0.001 NS Jacobsen et al KI 2003 N = 24 Type 1 DM DB X-Over 8 wks Enalapril 40 mgIrbesartan 300 mg 25% greater reduction in albuminuria 8/4 mmHg greater reduction in 24-h BP 64% greater reduction in renin < 0.001 < 0.031 < 0.05

13. CB-13 COOPERATE Trial 42 Study population263 pts with nondiabetic kidney disease Study designRun-in to determine maximum antiproteinuric ACEi dose (trandolapril 3 mg) then randomization to trandolapril 3 mg, losartan 100 mg, or both Primary outcomeDoubling of serum creatinine or ESRD Nakao N et al. Lancet 2003;361:117-124

14. CB-14 Proportion of Patients Reaching Endpoint COOPERATE Trial Nakao N et al. Lancet 2003;361:117-124 061218243036 30 25 20 15 10 5 0 Proportion reaching endpoint, % (renal failure or CrC×2) Combination Months after randomization Losartan Trandolapril 42 At risk, n Losartan89888479655947 Trandolapril86858375726358 Combination88878683767367 p = 0.018

15. CB-15 Change From Baseline in SBP, PCWP, and PADP at 0-Hr Trough After 4 Wk of Therapy Val-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) SBPPCWPPADP p = 0.013 2 0 –2 –4 –6 –8 –10 –12 Change in mm Hg Baruch L, et al. Circulation 1999;99:2658-2664.

16. CB-16 Change in Brain Natriuretic Peptide (BNP) From Baseline RESOLVD Pilot Study -10 0 10 Picogram/ml Candesartan 16 mg Candesartan 8 mg + enalapril 20 mg Enalapril 20 mg *p < 0.01 Adapted from McKelvie R, et al. Circulation 1999;100:1056-1064. 17 wk43 wk **

17. CB-17 Therapeutic Effects on End Systolic and End Diastolic Volumes RESOLVD Pilot Study 01743 Time, wk 01743 Time, wk Volume, mL McKelvie RS, et al. Circulation 1999;100:1056. Diastolic (Change in EDV) Systolic (Change in ESV) n = 768 Candesartan 4 - 16 mgEnalapril 20 mgCombo (Candesartan + Enalapril) p < 0.01 p < 0.05

18. CB-18 Benefits of Adding an ARB to an ACE Inhibitor Hamroff G, et al. Circulation 1999;99:990-992. Before RxMonth 3Month 6 12 13 14 15 16 17 Peak oxygen uptake ACEi + Placebo ACEi + Losartan 50 mg/d p < 0.02 Before RxMonth 3Month 6 2.0 2.5 3.0 3.5 4.0 NYHA functional class p < 0.01 ml/kg/min

19. 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?