Efficacy and Safety of Spironolactone in HFpEF and CKD

Study Questions:

What is the association between baseline kidney function and the net benefit of spironolactone in patients with heart failure (HF) with a preserved ejection fraction (HFpEF)?

Methods:

The study authors analyzed data from patients enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) Americas study (n = 1,767) to examine the association between the baseline estimated glomerular filtration rate (eGFR) and the primary composite outcome of cardiovascular death, HF hospitalization, or aborted cardiac arrest, as well as safety outcomes, including hyperkalemia, worsening kidney function, and permanent drug discontinuation for adverse events (AEs). In this analysis, the primary safety outcome was drug discontinuation due to an AE of persistent hyperkalemia (>5.5 mmol/L), worsening kidney function (creatinine levels >3.0 mg/dl), anaphylactic reaction or intolerance, or gynecomastia. The primary efficacy outcome was the primary TOPCAT study composite of cardiovascular death, HF hospitalization, or aborted cardiac arrest. They used Cox models to examine variations in the efficacy and safety of spironolactone according to eGFR.

Results:

The incidence of both the primary outcome (cardiovascular death, HF hospitalization, or aborted cardiac arrest) and drug-related AEs increased with declining eGFR. The incidence of the primary endpoint was 9.1 (95% confidence interval [CI], 7.9-10.5) per 100 patient-years in patients with an eGFR of ≥60 ml/min/1.73 m2, 10.6 (95% CI, 9.0-12.3) per 100 patient-years in patients with an eGFR of 45-60 ml/min/1.73 m2, and 18.4 (95% CI, 15.9-21.4) per 100 patient-years in patients with an eGFR of <45 ml/min/1.73 m2. Risk of the primary outcome was higher for patients with severe kidney dysfunction (eGFR <45 ml/ min/1.73 m2: hazard ratio, 1.99; 95% CI, 1.62-2.45; p < 0.001) compared to patients with relatively preserved eGFR (≥60 ml/min/1.73 m2).

Compared with placebo, across all eGFR categories, spironolactone was associated with lower relative risk for the primary efficacy outcome and for hypokalemia, but higher relative risk for hyperkalemia, worsening kidney function, and drug discontinuation. Spironolactone increased the absolute risk of worsening kidney function (absolute risk difference for total population, +9%; 95% CI, +4% to +14%; p < 0.001) and hyperkalemia (absolute risk difference for total population, +19%; 95% CI, +15% to +23%; p < 0.001), but not for creatinine values >3.0 mg/dl (absolute risk difference for total population, +2%; 95% CI, -2% to +6%; p = 0.44) compared with placebo. In addition, spironolactone decreased the absolute risk of hypokalemia (absolute risk difference for total population, -14%; 95% CI, -18% to -9%; p < 0001). The study authors also found that during 4-year follow-up, the absolute risk for AEs that prompted drug discontinuation was amplified in the lower eGFR categories, which suggested heightened risk for drug intolerance with declining kidney function.

Conclusions:

The study authors concluded that although consistent efficacy of spironolactone was observed across the range of eGFR, the risk of AEs was amplified in the lower eGFR categories. They also concluded that the use of spironolactone to treat HFpEF patients with advanced chronic kidney disease is supported only when close laboratory surveillance is possible.

Perspective:

This study is important because it suggests that worsening kidney function is not only associated with risk of increased AEs, particularly hyperkalemia with spironolactone, but also with worse outcomes. This study supports current recommendations of monitoring kidney function, particularly in those with underlying azotemia.

Clinical Topics: Arrhythmias and Clinical EP, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Implantable Devices, SCD/Ventricular Arrhythmias, Acute Heart Failure

Keywords: Anaphylaxis, Azotemia, Creatinine, Diuretics, Geriatrics, Glomerular Filtration Rate, Gynecomastia, Heart Arrest, Heart Failure, Hyperkalemia, Hypokalemia, Mineralocorticoid Receptor Antagonists, Outcome Assessment (Health Care), Renal Insufficiency, Chronic, Risk, Spironolactone, Stroke Volume


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