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Jim Hoehns, Pharm.D.
Classification
EF (%)
Description
HF with reduced EF
(HFrEF)
≤40
“systolic HF”; RCTs have mainly enrolled
these HF patients; only in these pts have
efficacious therapies been demonstrated
HF with preserved EF
(HFpEF)
≥50
“diastolic HF”; dx is challenging due to
excluding other noncardiac causes of
symptoms suggestive of HF; efficacious
therapies have not been identified
HFpEF, borderline
41-49
Characteristics, treatment patterns, and
outcomes appear similar to those of pts with
HFpEF
HFpEF, improved
>40
Subset of pts who previously had HFrEF

Randomized, double-blind trial, N=3,445
 Mean duration: 3.3 years
 Sponsor: NHLBI

Treatment
 Spironolactone
▪ 15mg QD; increased to max of 45mg/day by month 4
 Placebo

Outcome
 Primary: death from CV causes, aborted cardiac
arrest, or hospitalization for HF
 Endpoints adjudicated
N Engl J Med 2014;370:1383-92.

Inclusion criteria
 ≥ 50 years of age
 At least one sign of HF (at screening)
▪ PND, orthopnea, or dyspnea with exertion
 At least one symptom of HF (w/i 1 year)
▪ Rales, ↑JVD, edema, or + CXR (effusions, cardiomegaly)




LVEF ≥45%
BP: SBP <140 or SBP <160 (if on ≥3 BP meds)
K+ < 5.0
HF hospitalization within previous 12 months (nonadjudicated) OR BNP >100 or NT-proBNP >360

Exclusion criteria
 GFR <30 ml/min
 Scr ≥2.5 mg/dL
 COPD requiring steroids, home oxygen, or
hospitalized exacerbation within 1 yr

Stats
 Intention-to-treat
 Power: 80% to detect 20% relative reduction
 Assumption: 17.4% outcome rate at 3 yrs
▪ Target enrollment is 3,515

Enrollment (2006 – 2012); 233 sites – 6 countries
 USA: 1151
 Canada: 326
 Brazil: 167
 Argentina: 123
 Russia: 1066
 Georgia: 612

Dosage
 Mean dose: 25 mg/day

Discontinued study participation
 Spironolactone: 9.3%
 Placebo: 8.8%

Permanently discontinued study drug
 Spironolactone: 34.3%
 Placebo: 31.4%

SBP changes at 8 months
 Spironolactone: -2.7 mm Hg
 Placebo: -0.2 mm Hg (P<0.001)
Analysis of total HF
Hospitalizations:
Spiro: 6.8/100
person-years
Placebo: 8.3/100
person-years
(P=0.03)
Spironolactone did not reduce primary outcome
in HFpEF
 Adequately powered for primary outcome
 Spironolactone associated with 36% RRR in HF
hospitalizations among BNP enrolled stratum
 Were patients enrolled in Russia/Georgia (i.e.
more likely to be in prior HF hospitalization
stratum) less likely to have actual heart failure?
 If HFpEF and elevated BNP, spironolactone
worth consideration
