NYHA III* or IV heart failure ACE-I + loop diuretic ± digoxn RALES: Study Design NYHA III* or IV heart failure LVEF £ 35% ACE-I + loop diuretic ± digoxn 3 years Aldactone® 25 mg/day (n = 822) Placebo (n = 841) Primary Endpoint Total mortality Secondary Endpoint Cardiac mortality Cardiac hospitalization Cardiac mortality or cardiac hosptitalization Changes from baseline in NYHA classification Pitt et al, N Engl J Med, 1999. *History of NYHA IV within 6 months before first dose

RALES All-Cause Mortality

Combined Endpoint of Cardiac Mortality or Cardiac Hospitalization RALES Combined Endpoint of Cardiac Mortality or Cardiac Hospitalization

RALES Potassium Creatinine Systolic B.P. Heart Rate 6 160 140 114 120 110 113 109 110 110 100 5 80 4.53 4.57 60 4.34 40 4.24 4.21 4.25 20 4 Baseline Week 8 Month 24 Baseline Week 8 Month 24 Placebo Spironolactone 170 90 Systolic B.P. Heart Rate 160 86 150 81 81 140 82 80 79 78 78 130 122 123 123 124 122 122 78 120 74 110 100 70 Baseline Week 8 Month 24 Baseline Week 8 Month 24

Gynecomastia or Breast Pain (Males) RALES Adverse Events Gynecomastia or Breast Pain (Males) Serious Hyperkalemia (³ 6.0 mmol/L) 15 15 p <0.001 p = NS 10% 10 10 5 5 1.7% 1% 1.2% P S P S Pitt et al, N Engl J Med, 1999. Placebo Spironolactone

RALES Conclusion All-cause mortality 30% (p<0.001) Spironolactone used in conjunction with an ACE inhibitor provides significant beneifts in the treatment of advanced heart failure by reducing the risk of: All-cause mortality 30% (p<0.001) Cardiac mortality 31% (p<0.001) Hospitalization for heart failure 35% (p<0.001)