1. Jim Hoehns, Pharm.D.

2. ClassificationEF (%)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, borderline41-49Characteristics, treatment patterns, and outcomes appear similar to those of pts with HFpEF HFpEF, improved>40Subset of pts who previously had HFrEF

4.  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.

5.  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 (non- adjudicated) OR BNP >100 or NT-proBNP >360

6.  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

7.  Enrollment (2006 – 2012); 233 sites – 6 countries  USA: 1151  Canada: 326  Brazil: 167  Argentina: 123  Russia: 1066  Georgia: 612

11.  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)

15. Analysis of total HF Hospitalizations: Spiro: 6.8/100 person-years Placebo: 8.3/100 person-years (P=0.03)

20.  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