Higher absolute risk for adverse events with MRA in HFpEF patients in lower eGFR categories

Efficacy and Safety of Spironolactone in Patients With HFpEF and Chronic Kidney Disease

Literature - Beldhuis IE, Myhre PL, Claggett B et al. - JACC: Heart Failure 2019; 7(10):25-32

Introduction and methods

Guidelines recommendations indicate that the use of spironolactone may be considered in patients with symptomatic heart failure with preserved ejection fraction (HFpEF), elevated natriuretic peptides, an estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m2, creatinine<2.5 mg/dl, and potassium <5.0 mmol/l to reduce HF hospitalization [1-3]. However, it remains unknown whether the efficacy of spironolactone is consistent in HFpEF patients with chronic kidney disease, in whom safety concerns are most prominent. This post-hoc analysis (n=1.767) assessed the association between baseline renal function and the net benefit of spironolactone in patients with HFpEF included in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial (TOPCAT) trial who were enrolled in the Americas (U.S., Canada, Argentina, Brazil).

The international, double-blind, randomized, placebo-controlled, parallel-group TOPCAT trial (n=3.445) randomized symptomatic HFpEF patients with LVEF ≥45% (aged >50 years) to spironolactone or placebo over a mean follow-up duration of 3.3 years. Eligible patients had systolic blood pressure<140 mmHg at randomization, serum potassium of <5.0 mmol/L, and either a previous HF hospitalization within 12 months or an elevated natriuretic peptide level (BNP≥100 pg/mL or N-terminal pro-BNP ≥360 pg/mL). Participants were divided into three groups based on renal function by baseline: eGFR ≥60, 45-60, and 30-45 mL/min/1.73m².

The primary endpoint was the primary TOPCAT composite outcome of CV mortality, aborted cardiac arrest, or hospitalization for HF. The primary safety outcome was drug discontinuation due to an adverse event (AE) of persistent hyperkalemia (>5.5 mmol/l), worsening renal function (creatinine levels >3.0 mg/dl), anaphylactic reaction or intolerance, or gynecomastia.

Main results

Efficacy of spironolactone therapy

  • Consistent reduction of the primary endpoint was observed across the eGFR groups with spironolactone, compared to placebo (HR total population: 0.82, 95%CI: 0.69-0.98, P-interaction=0.13).
  • The efficacy of spironolactone remained consistent across the eGFR groups over 4-year follow-up, when examining absolute risk differences between spironolactone and placebo (-6%, 95%CI: -11% to -0.2%, P-interaction=0.23).

Safety of spironolactone therapy

  • In total population, spironolactone increased the absolute risk for worsening renal function (+9%, 95%CI: +4% to +14%, P<0.001) and hyperkalemia (+19%, 95%CI: +15% to +23%, P<0.001), but not for creatinine values >3.0 mg/dl (+2%, 95%CI: -2% to +6%, P=0.44), compared with placebo.
  • The absolute risk of hypokalemia was decreased with spironolactone in total population, compared with placebo (-14%, 95%CI: -18% to -9%, P<0.0001).
  • Median time to permanent discontinuation of spironolactone in TOPCAT-Americas was 704 days.
  • Spironolactone was consistently associated with higher relative risk for permanent study drug discontinuation due to AEs across all eGFR groups, compared with placebo (HR total population: 2.54; 95%CI: 1.91 to 3.37, P-interaction=0.46).
  • The difference in absolute risk for drug discontinuation due to AEs with spironolactone was amplified in patients with eGFR <45 and 45-60 mL/min/1.73m² (+27% [+12% to +42%] and +24% [+14% to +33%], respectively) (P-interaction=0.003), compared to those with an eGFR >60 mL/min/1.73m² (+8% [+3% to +14%]).


In this post-hoc analysis of the TOPCAT trial, spironolactone efficacy was consistent across baseline eGFR groups in HFpEF patients, however, during the 4-year follow-up, the difference in absolute risk for study drug discontinuation due to AEs with spironolactone was amplified in patients in lower eGFR categories, suggesting incremental risk with declining renal function. The authors suggest the need for close laboratory surveillance among patients with HFpEF and an eGFR <45 mL/min/1.73m² who are treated with spironolactone.

Editorial comment

In their editorial comment [4], Rossignol and Ferreira agree on the conclusion of Beldhuis et al. that use of spironolactone in patients with impaired renal function should only be considered when close laboratory surveillance is possible. They point to the specific monitoring regimen in the TOPCAT trial that consisted of definitive alarm thresholds for creatinine and potassium levels and corresponding actions (down-titration of drug discontinuation) and restart of the study drug in patients with improved hyperkalemia or worsening renal failure. The latter action is the key point of the regiment as it can prevent underuse of RAAS inhibitors and worse outcomes. RAASis are underused, suboptimally dosed and inadequately monitored in observational studies with HFrEF patients. Guidelines recommend close monitoring of potassium levels and renal function during titration of RAASis with down-titration or temporarily discontinuation for persistent hyperkalemia, hypotension or WRF and up-titration and re-initiation should be attempted as often as possible. The authors mention that unease regarding worsening renal function and hyperkalemia should not be used as a justification for suboptimal use of life-prolonging therapies. ‘These concerns should instead be positively converted to a firm commitment to perform mindful biological monitoring, aimed at retrieving, in the real-life setting, the best benefit of RAAS inhibitors observed in clinical trials. Such monitoring is even more compelling in patients with more advanced chronic kidney disease.’


1. Ezekowitz JA, O’Meara E, McDonald MA, et al. 2017 comprehensive update of the Canadian Cardiovascular Society guidelines for the management of heart failure. Can J Cardiol 2017;33: 1342–433.

2. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/ AHA guideline for the management of heart failure. J Am Coll Cardiol 2017;70:776–803.

3. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail 2016;18:891–975.

4. Rossignol P and Ferreira JP. Balancing Benefits and Risks of Spironolactone in HFpEF and Chronic Kidney Disease Patients. Mind the Gap of Biological Monitoring! JACC: Heart Failure 2019;7(1):33-5.

Find this article online at JACC: Heart Failure

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