TOPCAT - Spironolactone in HFpEF

Pitt B, et al. Spironolactone for heart failure with preserved ejection fraction. NEJM 2014;370:1383-92.

Bottom line: In patients with HFpEF, spironolactone did not reduce the risk of death or hospitalization over 3.3 years. Spironolactone does not noticeably improve quality of life in HFpEF.

Consistent with other "negative" studies in HFpEF, the results of TOPCAT supports the notion that patients with "HFpEF" should receive symptomatic treatment for HF, & interventions to reduce morbidity & mortality according to the underlying etiology. In this context, spironolactone remains useful for patients with HFpEF & resistant hypertension. The label of "HFpEF" does not yet offer an actionable management plan.

 

Context

  • Heart failure with preserved ejection fraction (HFpEF):
    • Defined as a clinical syndrome of signs & symptoms of HF with normal systolic function (LVEF >50% & LV end-diastolic volume index <97 mL/m^2) & evidence of diastolic LV dysfunction (relaxation, filling, diastolic distensibility or diastolic stiffness)
  • Interventions that reduce morbidity & mortality in HFrEF have not translated to benefits in HFpEF, including ACEIs & ARBs, beta-blockers & digoxin
  • Previous studies have demonstrated inconsistent results for aldosterone antagonists in HFpEF:
    • Aldo-DHF trial: In patients with HFpEF with a good prognosis, spironolactone improved E/e' (echo-derived surrogate for filling pressure), but not VO2 (stress test-derived measure of aerobic exercise capacity)
    • Cohort study: In patients with HFpEF, use of an aldosterone antagonist was not associated with reduced mortality or HF hospitalization

Patients (n=3445)

  • Inclusion
    • Age 50+
    • Clinical HF
    • LVEF >45% (measured within 6 months prior to randomization & after any prior ACS)
    • Controlled SBP (<140, or <160 if receiving 3+ antihypertensives)
    • Either,
      • 1+ HF-related hospitalization in prior 12 months, or
      • BNP >100 pg/mL (or N-terminal pro-BNP >360 pg/mL) within 30 days, not explained by another disease entity
  • Exclusion
    • Pericardial constriction
    • Hemodynamically significant uncorrected primary valvular heart disease
    • Infiltrative or hypertrophic obstructive cardiomyopathy (HoCM)
    • Stroke, MI or CABG in past 90 days
    • AF with resting HR >90 bpm
    • Heart transplant recipient or currently implanted LVAD
    • Chronic pulmonary disease: Requiring home O2 or PO steroids, hospitalization for exacerbation within 12 months, or significant in the opinion of the investigator
  • "Average" patient
    • Age 69 y (age 75+ 27%)
    • Female 52%
    • White 89%
    • HFpEF characteristics
      • Hospitalization in last 12 months 71%
      • NYHA functional class I (3%), II (64%), III (33%), IV (<1%)
      • BNP 236
      • LVEF 56%
    • BP 130/80 mm Hg
    • Meds
      • Diuretic 80%
      • ACEI/ARB 85%
      • Beta-blocker 75%
      • ASA 65%
      • Statin 55%

Intervention

  • I: Spironolactone
    • Initial dose: 15 mg PO daily x4 weeks
    • If initial dose tolerated, increased to 30 mg daily
    • If HF still symptomatic at month 4, increased to 45 mg daily
  • C: Matching placebo
  • Monitoring: Measurement of SCr & serum K required <1 week after start or change of study drug dose

Results @ mean 3.3 years

  • Efficacy
    • Death: Spironolactone 14.6% versus placebo 15.9%, hazard ratio (HR) 0.91 (95% confidence interval 0.77-1.08)
    • Hospitalization for any cause: 44.5% vs 46%, HR 0.94 (0.85-1.04)
    • Primary outcome (CV death, aborted cardiac arrest, HF hospitalization): 18.6% vs 20.4%, HR 0.89 (0.77-1.04)
    • Quality of life
      • Kansas City Cardiomyopathy Questionnaire (KCCQ; 100-point scale, minimal clinically important difference -5): -1.86 vs placebo at 36 months (p=0.02)
      • No statistically or clinically significant differences in EQ5D-VAS or McMaster Overall Treatment Evaluation score
  • Safety
    • Serious adverse event: 48.5% vs 49.6%
    • Discontinuation of study drug: 34.3% vs 31.4%
    • Doubling of SCr: 10.2% vs 7% (NNH 32)
    • Hyperkalemia (serum K >5.5 mmol/L): 18.7% vs 9.1% (NNH 11)

Issues with internal validity?

  • Low risk of bias characteristics: Randomized, allocation-concealed, double-blind trial analyzed using intention-to-treat population
  • Unclear risk of bias: Loss-to-follow-up on vital status ~4% 
  • Subgroup analysis: Primary outcome varied based on region (Americas vs Russia/Georgia, p<0.001 for interaction)
    • Americas: Spironolactone 10.4% vs placebo 12.6%, HR 0.82 (0.69-0.98)
    • Russia/Georgia: 9.3% vs 8.4%, HR 1.10 (0.79-1.51)
    • Credibility of this subgroup effect has been increased by a substudy demonstrating that participants from Russia were far more likely than those from North America to have no detectable serum concentrations of spironolactone metabolites. This indicates that significantly more participants from Russia did not receive the study drug, and raises the potential of misconduct at these study sites. Therefore, the results of the 'Americas' subgroup may be the most accurate reflection of the effect of spironolactone in HFpEF.
    • Secondary outcomes from the Americas subgroup:
      • Death: 6.5% vs 7.7%, HR 0.83 (0.68-1.02)
      • All-cause hospitalization: 32.9% vs 35.8%, HR 0.94 (0.83-1.05)
        • HF hospitalization: 7.9% vs 9.7%, HR 0.82 (0.67-0.99)
        • Hyperkalemia: 25.2% vs 8.9%
    • Exclusion of the Russia/Georgia participants renders the primary outcome statistically significant, but does not materially affect the effect estimate for the primary or secondary outcomes. Additionally, TOPCAT still fails to demonstrate a significant reduction in death or all-cause hospitalizations.