Specialty: cardiology,CHF
Problem: CCF (NYHA III & IV)
Participants: 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 μmol per liter)
Serum potassium concentration of more than 5.0 mmol per liter
Intervention: Spironolactone
Control: Placebo
Follow-up: Mean 24 months
Primary endpoint:
Death from any cause
Secondary endpoint(s):
Death from cardiac causes
Hospitalization 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
Results:
- Early termination of the trial due to significant (30%) reduction in the mortality in the
Spironolactone ara. (p<0.001)
- Significant reduction in sudden death and all cause mortality
- Improvement in the NYHA class inependent of age, etiology of HF and other therapy.
Original Paper:
The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators
2 Sep 1999 N Engl J Med. 1999 Sep 2;341(10):709-17.: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.
Deaths Per all causes:
Kaplan Meier Survival Curve - Spironolactone versus Placebo+standard therapy.
Special Points:
Participants with serum creatinine > 2.5 mg/dl were excluded.
Hyperkalemia was defined as potassium > 6.0
Hypokalemia as K+ < 3.0
Initial starting dose of spironolactone was 25 mg daily and topped at 50 mg daily.
Investigators waited till creatinine to hit 4 md/dl before they stopped spironolactone. (provided starting creatinine was less than 2.5).
Majority of participants (>85%) were caucasians and majority males (>70%).
Average EF 25%.
Almost equal number of ischemic and non-ischemic participants.
Almost > 90% were on ACEI.
Only 10% were on beta blockers.
41% percent participants had improvement in their NYHA class of HF.
Gynecomastia occured in 10% of patients.
SUMMARY SLIDE:
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