Using Spironolactone for HFpEF Lessens Risk of CV Death Despite Worsening Renal Function

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The researcher’s goal was to study the relationship between worsening renal function, spironolactone treatment, and clinical outcomes in patients with heart failure with preserved ejection fraction.

Patients with heart failure with preserved ejection fraction (HFpEF) who were treated with spironolactone had increased risk for worsening renal function (WRF) but decreased risk for cardiovascular (CV) death. These findings from a randomized, double-blind, placebo-controlled, parallel-group study were published in the Journal of the American College of Cardiology.

Patients (N=1767) with HFpEF living in the Americas were recruited for the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial (TOPCAT) study. WRF was defined by a doubling of baseline creatinine levels or a relative decrease in estimated glomerular filtration rate (eGFR). Participants were assessed for mortality, CV death, aborted cardiac arrest, or HF hospitalization at an average of 3.3 years.

Median creatinine was 1.1 (interquartile range [IQR], 0.9-1.4) mg/dl and eGFR was 57.9 (IQR, 45.1-73.6) ml/min/1.73 m2 at baseline. At study conclusion, 14.7% of patients had WRF. Stratified by renal function, those with WRF had a higher proportion of New York Heart Association (NYHA) functional class III/IV (P <.001), had lower serum potassium (P <.001), were more likely to be on b-blockers (P =.004), were heavier (P =.007), were more likely to be taking diuretic agents (P =.008), and had higher systolic blood pressure (P =.009).

WRF was associated with NYHA functional class (placebo arm: hazard ratio [HR], 2.05; 95% CI, 1.45-2.91; P <.001), diabetes (HR, 1.72; 95% CI, 1.33-2.23; P <.001), spironolactone (HR, 1.71; 95% CI, 1.30-2.24; P <.001), angiotensin receptor blockers or angiotensin-converting enzyme inhibitors (spironolactone arm: HR, 1.91; 95% CI, 1.18-3.11; P =.009), current smoking (HR, 1.63; 95% CI, 1.03-2.57; P=.04), and b-blockers (HR, 1.57; 95% CI, 1.11-2.21; P =.01).

Decreased WRF was associated with hemoglobin concentration (per 1 g/dl; HR, 0.83; 95% CI, 0.77-0.90; P <.001), potassium levels (per 1 mEq/l; HR, 0.61; 95% CI, 0.46-0.82; P =.001), and creatinine (spironolactone arm: HR, 0.52; 95% CI, 0.31-0.85; P =.01).

The risk for the composite endpoint was double among patients with WRF (incidence rate [IR], 21.2 vs 10.9 per 100 patient-years [py]) and risk for HF hospitalization (IR, 15.2 vs 8.4 per 100 py), CV death (IR, 12.1 vs 3.5 per 100 py), and all-cause mortality (IR, 15.1 vs 6.0 per 100 py) were all elevated among patients with WRF compared with patients without WRF, respectively.

Stratified by treatment arm, significant treatment interactions were observed for CV death (P =.003) and all-cause mortality (P =.001): Risks were decreased among patients who had WRF and received spironolactone compared with those who received a placebo and had WRF.

These findings may have been prone to type 1 errors due to the fact that this analysis was a subset of the entire TOPCAT study population.

These data indicated patients with HFpEF treated with spironolactone were associated with WRF but with lower risk for CV death and all-cause mortality compared with placebo recipients.

Disclosure: Several authors declared affiliations with the pharmaceutical industry. Please refer to the original article for a full list of authors’ disclosures.


Beldhuis IE, Myhre PL, Bristow M, et al. Spironolactone in patients with heart failure, preserved ejection fraction, and worsening renal function. J Am Coll Cardiol. 2021;77(9):1211-1221. doi:10.1016/j.jacc.2020.12.057