1. RALES: Randomized Aldactone Evaluation Study Purpose To determine whether the aldosterone antagonist spironolactone reduces mortality in patients with severe heart failure Reference Pitt B, Zannad F, Remme WJ et al. for the Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341: 709–17.

2. RALES: Randomized Aldactone Evaluation Study - TRIAL DESIGN - Design Multicenter, multinational, randomized, double-blind, placebo- controlled Patients 1663 patients in NYHA class III/IV who had been diagnosed with severe heart failure (NYHA class IV) <6 months previously, having left ventricular ejection fraction <35% and receiving an ACE inhibitor, loop diuretic and (most patients) digoxin Follow up and primary endpoint Mean 24 months follow up. Primary endpoint all-cause mortality Treatment Placebo or spironolactone 25 mg daily

3. RALES: Randomized Aldactone Evaluation Study - RESULTS - Trial stopped early because all-cause mortality significantly reduced in spironolactone group compared with placebo (35 vs. 46%, relative risk reduction 30%, P<0.001) Reduction in all-cause mortality: — attributed to significant reduction in sudden death and death due to progression of heart failure — similar across subgroups NYHA class improved (41 vs. 33%) or was unchanged (18 vs. 21%) in higher proportion of spironolactone group and worsened in lower proportion (48 vs. 38%), compared with placebo (P<0.001) Significantly more men in spironolactone group reported gynecomastia or breast pain, compared with placebo group Drug well tolerated as defined by withdrawal rate from trial: only marginally higher with spironolactone

4. RALES: Randomized Aldactone Evaluation Study - RESULTS continued - Months after randomization 0 0.40 841 822 Placebo Spironolactone No. at risk 723 739 628 669 565 608 379 419 179 193 36 43 61218243036 0.60 0.50 1.00 0.90 0.80 0.70 Survival Spironolactone Placebo Probability of survival P<0.001 Pitt et al. N Eng J Med 1999; 341: 709–17.

5. RALES: Randomized Aldactone Evaluation Study - RESULTS continued - P Total Cardiac causes Progression of heart failure * Sudden death MI Other cardiovascular causes Stroke Noncardiovascular causes Unknown Cause of death 45.9 37.3 22.5 13.1 1.8 1.6 1.3 4.9 0.8 34.6 27.5 15.5 10.0 2.1 1.5 6.6 3.5 1.1 0.70 (0.60–0.82) 0.69 (0.58–0.82) 0.64 (0.51–0.80) 0.71 (0.54–0.95) <0.001 0.02 Relative risks and causes of death Placebo n=841 (%) Spironolactone n=822 (%) Relative risk (95% CI) Pitt et al. N Eng J Med 1999; 341: 709–17. * Including death due to worsening HF (increasing symptoms/signs, requiring increase in treatment)

6. RALES: Randomized Aldactone Evaluation Study - RESULTS continued - 0.20.8 Relative risk of death 0.40.61.0 Effect of spironolactone on subgroups Spironolactone betterPlacebo better 1.21.4 Pitt et al. N Eng J Med 1999; 341: 709–17. Death from all causes Median age:<67 years >67 years LV ejection fraction: <26% >26% Cause of heart failure: Nonischemic Ischemic NYHA class: III IV Digitalis: No Yes ACE inhibitor: No Yes Beta-blocker:No Yes

7. RALES: Randomized Aldactone Evaluation Study - RESULTS continued - P Discontinuation because of adverse event Cardiovascular disorders Angina Heart failure Endocrine disorders * Gynecomastia in men Breast pain in men 40 (5) 251 (30) 83 (10) 80 (10) 8 (1) 1 (0.1) 62 (8) 248 (30) 103 (13) 52 (6) 55 (9) 10 (2) <0.001 0.006 Adverse events Placebo n=841 No. (%) Spironolactone n=822 No. (%) Pitt et al. N Eng J Med 1999; 341: 709–17. * 614 men in placebo group; 603 in spironolactone group.

8. RALES: Randomized Aldactone Evaluation Study - SUMMARY - In patients with severe heart failure and left ejection fraction <35%, spironolactone reduced: All-cause mortality Sudden death and death due to progression of heart failure Benefit was independent of age, ejection fraction, cause of heart failure and concurrent therapy