Heart failure: spironolactone reduced death and hospitalisation

Clinical bottom line (level 1b)

  1. Patients with severe heart failure who took spironolactone compared with placebo were less likely to die (NNT = 9 at 24 months) or be hospitalised (NNT = 11 at 24 months) .
  2. Patients on spironolactone were less likely to be hospitalised with worsening heart failure (NNT = 11 at 24 months) and were more likely to have an improvement in their symptoms (NNT = 13 at 24 months) .
  3. There was no difference in overall adverse events, but men on spironolactone are more likely to develop gynaecomastia (NNH = 17 at 24 months) , and more patients on spironolactone were likely to withdraw due the adverse events (NNH = 36 at 24 months) .
  4. There was no clear difference in the number of patients developing severe hyperkalaemia.
Pitt et al: New England Journal of Medicine 1999; 341: 709-717
Expires October 2003

The study

Double-blinded ?concealed randomised trial with intention-to-treat
Setting: 195 acute hospitals in 15 countries in Europe, North America, Japan, New Zealand and South Africa

1663 patients (aged mean 65, 73% male) with
  • severe heart failure (NYHA class IV within last 6 months and currently NYHA class III or IV)
  • diagnosis of heart failure at least 6 weeks before enrolment
  • on ACE inhibitor and a loop diuretic
  • left ventricular ejection fraction < 35% within last 6 months


Excluded if
  • active cancer
  • any life-threatening condition
  • awaiting or undergone heart transplantation
  • serum creatinine > 221 micromol/l
  • serum potassium > 5.0 mmol/l
  • on oral potassium-sparing diuretic
  • primary operable valvular heart disease (other than mitral or tricuspid regurgitation with clinical symptoms due to left ventricular systolic heart failure)
  • congenital heart disease
  • unstable angina
  • primary hepatic failure


Note:
  • Treatment with digitalis and vasodilators was allowed (74% digoxin; 95% ACE inhibitors). Oral potassium supplements were not recommended unless potassium was < 3.5 mmol/l


Control Group: (n = 841, 841 analysed): placebo
Experimental Group: (n = 822, 822 analysed): oral spironolactone 25 mg once daily, increased to 50 mg once daily if signs of symptoms of progressive heart failure without hyperkalaemia.
Study medication could be withheld if there was severe hyperkalaemia, a creatinine > 354 micromol/l, intercurrent illness or any condition in which such a course was thought medically necessary.
100% followed for 24 months
Outcome notes:
  • severe hyperkalaemia : potassium > 6.0 mmol/l

The evidence

Outcome Time to outcome CEREERRRR
(95% CI)		ARR
(95% CI)		NNT
(95% CI)
death 24 months 386
(45.9%)		 284
(34.6%)		 25%
(15% to 33%)		 11.4%
(6.67% to 16.0%)		 9
(6 to 15)
hospitalisation for cardiac causes 24 months 336
(40%)		 260
(31.6%)		 21%
(10% to 30%)		 8.32%
(3.7% to 12.9%)		 12
(8 to 27)
hospitalisation due to worsening heart failure 24 months 300
(35.7%)		 215
(26.2%)		 27%
(15% to 37%)		 9.52%
(5.10% to 13.9%)		 11
(7 to 20)
improvement in NYHA class 24 months 278
(33.1%)		 337
(41.0%)		 24%
(9% to 41%)		 7.94%
(3.31% to 12.6%)		 13
(8 to 30)
adverse effects 24 months 667
(79.3%)		 674
(82.0%)		 -3%
(-8% to 1%)		 -2.68%
(-6.48% to 1.11%)		 -37
(NNT = 15 to infinity;
NNH = 90 to infinity)
discontinuation of medication due to adverse event 24 months 40
(4.76%)		 62
(7.54%)		 -59%
(-130% to -8%)		 -2.79%
(-5.09% to -0.48%)		 -36
(-210 to -20)
gynaecomastia in men 24 months 8
(0.95%)		 55
(6.69%)		 -600%
(-1370% to -240%)		 -5.74%
(-7.57% to -3.91%)		 -17
(-26 to -13)
severe hyperkalaemia 24 months 10
(1.19%)		 14
(1.70%)		 -43%
(-220% to 36%)		 -0.51%
(-1.66% to 0.63%)		 -200
(NNT = 60 to infinity;
NNH = 160 to infinity)

Comments

  1. The study is too small to show any difference between the two groups for severe hyperkalaemia.
  2. Aldosterone causes myocardial and vascular fibrosis, direct vascular damage, baroreceptor dysfunction and prevents the uptake of norepinephrine by myocardium. Spironolactone could be cardioprotective by blocking formation of collagen-induced by aldosterone. Myocardial fibrosis may predispose ventricular arrhythmias.

Citation

  1. Pitt B, Zannad F, Remme WJ, et al: the effect of spironolactone on morbidity and mortality in patients with severe heart failure (RALES). New England Journal of Medicine 1999; 341: 709-717
Contributor: Arturo Marti-Carvajal; Chris Ball, October 1999
Reviewer: Bruce Arroll

Clinical Question.
Patient severe heart failure
Intervention or Exposure spironolactone
Comparison placebo
Outcome death, hospitalisation, improvement in symptoms, adverse events