Journal Club

Jim Hoehns, Pharm.D.

HFrEF and HFpEFClassification EF (%) DescriptionHF 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

TOPCAT - HFpEF 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 adjudicatedN Engl J Med 2014;370:1383-92.

TOPCAT - Methods 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

TOPCAT – Methods

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

TOPCAT - Methods

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

TOPCAT - Results 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)

TOPCAT – Dosage at 8 Months

Analysis of total HFHospitalizations:

Spiro: 6.8/100person-yearsPlacebo: 8.3/100 person-years(P=0.03)

Subgroup Analyses by Randomization

Subgroup Analyses by Region

Early Permanent Drug Discontinuation

Reasons for Drug Discontinuation

Summary 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