Race influences the safety and efficacy of spironolactone in severe heart failure

Background-The incidence of hyperkalemia caused by mineralocorticoid receptor antagonists may vary by race, but whether race influences efficacy of mineralocorticoid receptor antagonists in heart failure (HF) is unknown. Methods and Results-We assessed hyperkalemia and outcomes in African Americans (AAs; n=120) and non-AAs (n=1543; white 93%) with New York Heart Association (NYHA) class III or IV HF and left ventricular dysfunction who were randomized to spironolactone, titrated to 25 or 50 mg daily or placebo, in the Randomized Aldactone Evaluation Study (RALES). AA participants were significantly younger, less likely to have an ischemic HF pathogenesis, more likely to be NYHA functional class IV, and more likely to have a higher estimated glomerular filtration rate and heart rate, less hypertension, diabetes mellitus, or history of myocardial infarction compared with non-AA participants. Potassium increased with spironolactone in non-AAs (4.29±0.5-4.55±0.49 mmol/L) but not in AAs (4.32±0.54-4.31±0.49 mmol/L; race by treatment interaction, P=0.03) during the first month and remained higher throughout the trial. Compared with AAs, non-AAs were more likely to attain maximal spironolactone dose (13.9% versus 5.8%; P=0.04) and had higher rates of hyperkalemia (potassium>5.5 mmol/L; 9.7% versus 4.2%; P<0.046), as well as lower rates of hypokalemia (potassium<3.5 mmol/L; 5.6% versus 17.9%; P<0.001). After adjustment for differences in baseline characteristics and achieved study drug dose, spironolactone reduced the combined end point of death or hospitalization for HF in non-AAs (hazard ratio, 0.63; 95% confidence interval, 0.55-0.73) but not in AAs (hazard ratio, 1.07; 95% confidence interval, 0.67-1.71; P value for interaction=0.032). Conclusions-AAs with HF exhibited less hyperkalemia and more hypokalemia with spironolactone compared with non- AAs and seemed to derive less clinical benefit. These hypothesis-generating findings suggest that safety and efficacy of mineralocorticoid receptor antagonists may differ by race.