The Fine Art and Science of Translating Trials Results Into Clinical Practice

Over 2 decades ago, the mineralocorticoid receptor antagonist (MRA), spironolactone was demonstrated to substantially reduce the risk of all-cause mortality along with heart failure (HF) hospitalizations in patients with HF with reduced ejection fraction (HFrEF) enrolled in the Randomized Aldactone Study (RALES) trial. Under trial selection and protocol-directed monitoring, the median potassium (0.30 mmol/L) and creatinine levels (0.10 mg/dL) increased modestly with spironolactone relative to placebo. Serious hyperkalemia as an adverse event did not differ. However, after publication of the RALES trial, a series of reports suggested that as applied in clinical practice, rates of hyperkalemia and hyperkalemia hospitalizations with MRAs were much higher than expected. Subsequent studies identified that patients frequently started doses of spironolactone without consideration of baseline kidney function, without subsequent laboratory monitoring, or when tested potassium levels were elevated without timely adjustment in dosing. As a result of these reports and the continued perception of hyperkalemia risk, MRAs have continued to be underused in eligible patients with HFrEF.