Spironolactone for Heart Failure with Preserved Ejection Fraction (TOPCAT)

Authors, Journal, Affiliations, Type, DOI

• Bertram Pitt, Marc A. Pfeffer, Susan F. Assmann, and TOPCAT Investigators
• New England Journal of Medicine, 2014; 370(15):1383–1392
• 233 sites in 6 countries (US, Canada, Brazil, Argentina, Russia, Georgia)
• Phase 3, multicentre, international, randomised, double-blind, placebo-controlled trial
• Funded by NHLBI/NIH (not industry)
• DOI: https://doi.org/10.1056/NEJMoa1313731

Overview

TOPCAT was a multicentre double-blind RCT enrolling 3,445 patients with symptomatic HFpEF (LVEF ≥45%) randomised to spironolactone (15–45 mg/day) vs placebo over a mean 3.3-year follow-up. The primary composite of CV death, aborted cardiac arrest, or HF hospitalisation was not significantly reduced (HR 0.89; P=0.14), but HF hospitalisation alone was significantly lower with spironolactone (HR 0.83; P=0.04). A critical post-hoc integrity concern — spironolactone metabolites (canrenone) detectable in only ~38% of Russian "active-treatment" participants vs >90% in the Americas — suggests widespread placebo dispensing in Russia and Georgia, which diluted the true treatment effect in the overall trial. The Americas-only subgroup and BNP-stratum analyses both showed meaningful benefit, informing current COR 2b/Class IIb guideline recommendations for MRA in HFpEF.

Keywords

Spironolactone, HFpEF, mineralocorticoid-receptor antagonist, aldosterone antagonist, heart failure, preserved ejection fraction, MRA

Key Takeaways

Study Design and Population

• n=3,445: spironolactone 1,722 vs placebo 1,723; 1:1 double-blind; ITT analysis
• 233 sites; 6 countries: US 1,151; Canada 326; Brazil 167; Argentina 123; Russia 1,066; Georgia 612
• Enrolled August 2006 – January 2012; mean follow-up 3.3 years
• Inclusion: Age ≥50; LVEF ≥45%; ≥1 HF sign + ≥1 symptom; controlled SBP; serum K <5.0 mmol/L
• Entry stratum: Hospitalisation stratum (71.5%, prior HF hospitalisation within 12 months) OR BNP stratum (28.5%; BNP ≥100 or NT-proBNP ≥360 pg/mL)
• Spironolactone dose: started at 15 mg, titrated to maximum 45 mg/day (mean 25 mg at 8 months)
• ~34% of spiro group discontinued study drug during trial (vs 31% placebo)

Primary Endpoint — Composite of CV Death, Aborted Cardiac Arrest, HF Hospitalisation

• Spiro: 320/1,722 (18.6%); Placebo: 351/1,723 (20.4%)
• HR 0.89 (95% CI 0.77–1.04; P=0.14) — NOT significant
• Event rates: 5.9 vs 6.6 per 100 person-years

Component Outcomes

• CV death: 9.3% vs 10.2%; HR 0.90 (95% CI 0.73–1.12; P=0.35) — NS
• Aborted cardiac arrest: 0.2% vs 0.3% — NS
• HF hospitalisation (first event): 12.0% vs 14.2%; HR 0.83 (95% CI 0.69–0.99; P=0.04) — significant
• Total HF hospitalisations (including recurrent): 394 vs 475; 6.8 vs 8.3/100 person-years; P=0.03 — significant
• All-cause mortality: HR 0.91 (95% CI 0.77–1.08; P=0.29) — NS
• Total hospitalisations (any cause): 36.8 vs 36.3/100 person-years; P=0.71 — NS

Stratum Interaction (Pre-specified, P=0.01)

• Hospitalisation stratum: HR 1.01 (95% CI 0.84–1.21; P=0.92) — no benefit
• BNP stratum: HR 0.65 (95% CI 0.49–0.87; P=0.003) — significant benefit
• BNP-stratum patients were older, had higher creatinine, lower K, lower eGFR, and were less likely to be from Russia/Georgia

Regional Variation (Post-hoc)

• Americas (US, Canada, Brazil, Argentina): 27.3% (spiro) vs 31.8% (placebo) — benefit visible
• Russia and Georgia: 9.3% (spiro) vs 8.4% (placebo) — no gradient; extremely low event rates
• Pre-specified region × treatment interaction: P=0.12 (NS in this paper)
• Post-hoc Americas analysis (Pfeffer et al. 2015, Circulation): HR ~0.82; P=0.026

Data Integrity Concern — Russia/Georgia

• Post-hoc metabolite analysis (Pfeffer et al. 2015, Circulation): spironolactone metabolite canrenone detected in only ~38% of Russian "active treatment" participants vs >90% in the Americas
• Suggests widespread dispensing of placebo instead of active drug in Russia/Georgia
• The anomalously low event rates in Russia/Georgia placebo group (8.4%) compared with Americas placebo (31.8%) supports this interpretation — either patients were not truly HFpEF, or placebo was given in both arms
• This integrity problem is the principal reason TOPCAT's primary endpoint was neutral and why the Russia/Georgia-inclusive analysis should be interpreted with caution

Safety

• Hyperkalemia (K ≥5.5): 18.7% (spiro) vs 9.1% (placebo) — doubled
• Hypokalemia (K <3.5): 16.2% vs 22.9% — reduced (protective)
• Creatinine doubling: 10.2% vs 7.0%
• Creatinine ≥3.0 mg/dL: no significant difference; dialysis: no significant difference
• Gynecomastia/breast tenderness: significantly higher with spironolactone
• Systolic BP lower at post-baseline visits with spironolactone

Limitations of the document

• Data integrity problem in Russia/Georgia (widespread non-dispensing of active drug) confounds the primary analysis — this is not acknowledged in the original paper but was demonstrated in a 2015 follow-up analysis
• ~34% drug discontinuation rate dilutes the ITT treatment effect
• Stratum heterogeneity (hospitalisation vs BNP) with significant interaction — overall result is a blend of two biologically distinct populations
• Pre-specified region × treatment interaction was not significant (P=0.12), limiting formal claims about Americas benefit
• Open-label doses (15–45 mg) with titration variability; mean achieved dose 25 mg — similar to RALES
• LVEF threshold ≥45% used; current guidelines use ≥50% — some enrolled patients may have had HFmrEF
• Enrolled before SGLT2i era; no assessment of incremental MRA benefit on top of SGLT2i background therapy

Key Concepts Mentioned

• concepts/Cardiorenal-Syndrome — hyperkalemia and creatinine rise with MRA in HFpEF; monitoring requirements

Key Entities Mentioned

• entities/HFpEF — primary disease context; basis for COR 2b/IIb MRA recommendation
• entities/Heart-Failure — HFpEF management hub

Wiki Pages Updated

• wiki/sources/spironolactone-hfpef-topcat-nejm-2014.md — created
• wiki/entities/HFpEF.md — TOPCAT subsection added; MRA line enriched; contradiction added; source_count 12→13
• wiki/entities/Heart-Failure.md — HFpEF MRA line enriched with TOPCAT citation
• wiki/sourceindex.md — new entry
• wiki/wikiindex.md — HFpEF entry updated