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RALES: Randomized Aldactone Evaluation Study

RALES: Randomized Aldactone Evaluation Study. Purpose To determine whether the aldosterone antagonist spironolactone reduces mortality in patients with severe heart failure Reference

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RALES: Randomized Aldactone Evaluation Study

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  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 - Survival Probability of 1.00 survival Spironolactone 0.90 Placebo 0.80 0.70 0.60 0.50 P<0.001 0.40 0 6 12 18 24 30 36 Months after randomization No. at risk Placebo 841 723 628 565 379 179 36 Spironolactone 822 739 669 608 419 193 43 Pitt et al. N Eng J Med 1999; 341: 709–17.

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

  6. RALES: Randomized Aldactone Evaluation Study- RESULTS continued - Effect of spironolactone on subgroups Spironolactone better Placebo better 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 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Relative risk of death Pitt et al. N Eng J Med 1999; 341: 709–17.

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

  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

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