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Journal Club

Jim Hoehns, Pharm.D. Journal Club. HF r EF and HF p EF. TOPCAT - HF p EF. 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

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Journal Club

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  1. Jim Hoehns, Pharm.D. Journal Club

  2. HFrEF and HFpEF

  3. 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 adjudicated N Engl J Med 2014;370:1383-92.

  4. 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) ORBNP >100 or NT-proBNP >360

  5. 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

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

  7. 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)

  8. TOPCAT – Dosage at 8 Months

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

  10. Subgroup Analyses by Randomization

  11. Subgroup Analyses by Region

  12. Early Permanent Drug Discontinuation

  13. Reasons for Drug Discontinuation

  14. 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

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