Impact of eplerenone on cardiovascular outcomes in heart failure patients with hypokalaemia

Abstract Aims Although hypokalaemia is common among patients with heart failure ( HF ), the prognostic significance of baseline hypokalaemia and hypokalaemia during follow‐up in HF patients receiving a mineralocorticoid receptor antagonist ( MRA ) remains uncertain. Methods and results Results of the EMPHASIS‐HF trial in patients ( n = 2737) with HF and reduced EF with mild symptoms, randomized to eplerenone or placebo, were analysed with regard to the presence or occurrence of hypokalaemia (serum K + <4.0 mmol/L) and the risk of cardiovascular death or hospitalization for HF (primary endpoint). Median follow‐up was 21 months. Baseline hypokalaemia and hypokalaemia during follow‐up were common occurrences (19.6% and 40.6%, respectively). Hypokalaemia during follow‐up was associated with worse outcomes in multivariable analyses [hazard ratio ( HR ) 1.26, 95% confidence interval ( CI ) 1.05–1.52, P = 0.01] without evidence of interaction with eplerenone. In contrast, baseline hypokalaemia was associated with outcomes in the placebo group ( HR 1.37, 95% CI 1.05–1.79, P = 0.02) but not in the eplerenone group ( HR 0.87, 95% CI 0.62–1.23, P = 0.44; P for interaction = 0.04). Concurrently, eplerenone was found to be more protective in patients with baseline hypokalaemia vs. patients without baseline hypokalaemia compared with placebo ( HR 0.44, 95% 0.30–0.64, P < 0.0001 vs. 0.69, 95% CI 0.57–0.83, P = 0.0001; P for interaction = 0.04). In patients without baseline hypokalaemia, eplerenone use decreased the rate of hypokalaemia during follow‐up ( HR 0.69, 95% CI 0.59–0.80, P < 0.001). A potassium level >4.0 mmol/L at 1 month after randomization mediated 26.0% (0.6–51.4%) of the eplerenone treatment effect ( P = 0.04). Conclusion In HF patients receiving optimal therapy but not treated with eplerenone, baseline hypokalaemia was associated with worse outcomes. Conversely, hypokalaemia amplified the treatment effect of eplerenone.