Problem CCF (NYHA III & IV)
Format Double-blinded multi-center RCT
Treatment Spironolactone
Control Placebo
Population 1663
Inclusion criteria Must have all of:

New York Heart Association (NYHA) class IV heart failure within the six months before enrolment
In NYHA class III or IV at the time of enrolment
Diagnosis of heart failure at least six weeks before enrolment
Being treated with an ACE inhibitor (if tolerated) and a loop diuretic
Had a left ventricular ejection fraction of no more than 35 percent within the six months before enrollment (with no clinically significant intercurrent event)

Treatment with digitalis and vasodilators was allowed, but potassium-sparing diuretics were not permitted.
Exclusion criteria 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
Active cancer
Any life-threatening disease (other than heart failure)
Those undergone or awaiting heart transplant
Serum creatinine concentration of more than 2.5 mg per deciliter (221 Î_mol per liter)
Serum potassium concentration of more than 5.0 mmol per liter
Follow-up Mean 24 months
Primary endpoint Death from any cause
Secondary endpoint(s) Death from cardiac causes
Hospitalisation for cardiac causes
Combined incidence of death from cardiac causes or hospitalization for cardiac causes
Change in NYHA class

The effect of spironolactone was also assessed with the use of six prerandomization variables: left ventricular ejection fraction, the cause of heart failure, the serum creatinine concentration, age, the use of ACE inhibitors, and the use of digitalis.
Details Patients started on 25mg, could be uptitrated to 50mg @ 8 weeks if progression of disease without hyperkalaemia

If patients developed hypokalaemia, dose reduced to 25mg alternating days - however, advice was to adjust other medications first
Brief summary: Spironolactone reduced mortality and symptoms in NYHA 3+
PAPER: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators
Date 2 Sep 1999
Journal N Engl J Med. 1999 Sep 2;341(10):709-17.
Information Trial stopped early due to 30% relative risk reduction (p<0.001)

In patients with severe HF and LVEF < 35%, spironolactone vs. placebo:
-Significant reduction in all cause mortality
--Significant reduction in sudden death and progression of CCF
--Similar across all subgroups
-NYHA improved significantly more and worsened in significantly fewer

Benefits independent of age, EF, aetiology of HF and other therapy