Mineralocorticoid Receptor Antagonists and Empagliflozin in HFpEF
- In a post hoc analysis of the EMPEROR-Preserved trial, the effect of empagliflozin in lowering the risk for composite of HF hospitalization and cardiovascular mortality was no different by MRA use status.
- Empagliflozin reduced HF hospitalizations to a greater extent in MRA nonusers than MRA users.
- Empagliflozin reduced the incidence of hyperkalemia in MRA users.
What is the influence of mineralocorticoid receptor antagonists (MRAs) on the effect of empagliflozin in patients with heart failure with preserved ejection fraction (HFpEF)?
This was a post hoc analysis of the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction) trial. Enrolled patients had chronic HF with left ventricular ejection fraction >40% and New York Heart Association (NYHA) class II-IV symptoms with an elevated B-type natriuretic peptide (BNP)/NT-proBNP or evidence of structural heart disease or documented HF hospitalization within the past year. Patients were randomized to placebo or empagliflozin. The primary endpoint was a composite of cardiovascular death and HF hospitalization. Use of an MRA was not mandated.
A total of 5,988 patients were enrolled in the EMPEROR-Preserved trial with 2,244 (37.5%) receiving MRA at baseline. Patients on MRA were younger with a lower blood pressure, higher prevalence of diabetes, previous HF hospitalization within the past year, NYHA class III or IV, and on loop diuretics. Empagliflozin reduced the composite of HF hospitalization or cardiovascular mortality regardless of MRA use. Empagliflozin reduced HF hospitalizations more in MRA nonusers than in MRA users. However, empagliflozin did not reduce cardiovascular death in MRA users and MRA nonusers. Renal protection and improvement in health status (measured by Kansas City Cardiomyopathy Questionnaire [KCCQ] scores) by empagliflozin was similar in MRA users and nonusers. Randomization to empagliflozin did not modify initiation or discontinuation of MRA. Empagliflozin reduced incidence of hyperkalemia in MRA users.
In a post hoc analysis of the EMPEROR-Preserved trial, empagliflozin improved health status and had renoprotective effects in HFpEF patients regardless of MRA use. However, empagliflozin reduced HF hospitalizations to a greater extent in MRA nonusers than MRA users. Empagliflozin reduced incident hyperkalemia in MRA users.
The quest to find agents that modify the course of patients with HFpEF has been ongoing for the past several years. The TOPCAT trial that randomized HFpEF patients to MRA was unfortunately flawed by methodical errors, as in certain geographical regions, enrolled patients were not sick enough and had negligible levels of circulating drug metabolites. Accordingly, this uncertainty regarding benefit of MRA in HFpEF patients is shown by the fact that MRA was used only in 37% of patients in the EMPEROR-Preserved trial and these patients were sicker at baseline. In addition, MRA use is associated with a risk for hyperkalemia. Perhaps the most important finding of this post hoc analysis is that empagliflozin reduced the incidence of hyperkalemia in MRA users. However, reduction in the primary endpoint (composite of cardiovascular death and HF hospitalization) with empagliflozin was no different in MRA users and nonusers. These results suggest that it is safe to use empagliflozin and MRA. However, being a post hoc analysis, it is insufficient to rule out synergistic effects of these two agents, especially since patients receiving MRA were sicker at baseline.
Keywords: Blood Pressure, Diabetes Mellitus, Geriatrics, Health Status, Heart Failure, Hospitalization, Hyperkalemia, Mineralocorticoid Receptor Antagonists, Natriuretic Peptide, Brain, Pharmaceutical Preparations, Sodium Potassium Chloride Symporter Inhibitors, Stroke Volume, Ventricular Function, Left
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