RALES: Randomized Aldactone Evaluation Study

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 70917.

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) lt6 months previously, having left ventricular
  ejection fraction lt35 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, Plt0.001)
• 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
  (Plt0.001)
• 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
1.00
Probability of
survival
Spironolactone
0.90
Placebo
0.80
0.70
0.60
0.50
Plt0.001
0.40
0
6
12
18
24
30
36
Months after randomization
No. at risk
841
Placebo
723
628
565
379
179
36
822
Spironolactone
739
669
608
419
193
43
Pitt et al. N Eng J Med 1999 341 70917.
5
RALES Randomized Aldactone Evaluation Study-
RESULTS continued -

Relative risks and causes of death
Placebo
Spironolactone
Relative risk
P
n841
n822
(95 CI)
()
()
Cause of death
Total
45.9
34.6
0.70 (0.60

0.82)
lt0.001
Cardiac causes
37.3
27.5
0.69 (0.58

0.82)
lt0.001


Progression of heart failure
22.5
15.5
0.64 (0.51

0.80)
lt0.001
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 70917.
6
RALES Randomized Aldactone Evaluation Study-
RESULTS continued -

Effect of spironolactone on subgroups
Spironolactone better
Placebo better
Death from all causes
Median agelt67 years
gt
67 years
LV ejection fraction lt26
gt
26
Cause of heart failure Nonischemic
Ischemic
NYHA class III
IV
Digitalis No
Yes
ACE inhibitor No
Yes
Beta-blockerNo
Yes
0.2
0.8
0.4
0.6
1.0
1.2
1.4
Relative risk of death
Pitt et al. N Eng J Med 1999 341 70917.
7
RALES Randomized Aldactone Evaluation Study-
RESULTS continued -

Adverse events
Placebo
Spironolactone
P
n841
n822
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
lt0.001
8 (1)
55 (9)
Breast pain in men
1 (0.1)
10 (2)
0.006

Pitt et al. N Eng J Med 1999 341 70917.
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 lt35, 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