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Interplay of Mineralocorticoid Receptor Antagonists and Empagliflozin in Heart Failure: EMPEROR-Reduced
João Pedro Ferreira1, Faiez Zannad1, Stuart J Pocock2
1Université de Lorraine, INSERM, Centre d'Investigation Clinique et Plurithématique 1433, INSERM U1116, CHRU de Nancy, Cardiovascular and Renal Clinical Trialists, Nancy, France.
Insights
Mineralocorticoid receptor antagonists (MRAs) and empagliflozin are beneficial for heart failure. In the EMPEROR-Reduced trial, MRAs did not alter empagliflozin
Area of Science:
- Cardiology
- Pharmacology
- Clinical Trials
Background:
- Mineralocorticoid receptor antagonists (MRAs) and sodium glucose co-transporter 2 inhibitors (SGLT2i) improve outcomes in heart failure with reduced ejection fraction (HFrEF).
- Understanding the interplay between these drug classes is crucial for optimizing HFrEF management.
Purpose of the Study:
- To investigate the mutual influence of empagliflozin and MRAs in patients with HFrEF within the EMPEROR-Reduced trial.
- To assess whether MRA use modifies the efficacy and safety of empagliflozin.
Main Methods:
- Secondary analysis of the EMPEROR-Reduced trial, involving 3,730 patients with HFrEF.
- Comparison of empagliflozin versus placebo, stratified by MRA use at randomization (71% of patients were MRA users).
- Evaluation of effects on primary and secondary efficacy endpoints, safety outcomes, and MRA treatment patterns.
Main Results:
- Empagliflozin's effects on the primary endpoint, most efficacy measures, and safety were consistent regardless of MRA use (interaction p > 0.20).
- Trends for reduced cardiovascular and all-cause mortality with empagliflozin were observed in MRA users, though not statistically significant (interaction p=0.10 and p=0.098, respectively).
- Empagliflozin use was associated with reduced initiation of MRAs in non-users and reduced discontinuation of MRAs in users.
- Severe hyperkalemia was less frequent with empagliflozin.
Conclusions:
- MRA use did not influence the beneficial effects of empagliflozin on heart failure and renal outcomes in the EMPEROR-Reduced trial.
- Empagliflozin treatment facilitated the continued use of MRAs, potentially enhancing overall patient management.
- Empagliflozin demonstrated a favorable safety profile, including reduced severe hyperkalemia.
Background:
Mineralocorticoid receptor antagonists (MRAs) and sodium glucose co-transporter 2 inhibitors favorably influence the clinical course of patients with heart failure and reduced ejection fraction.
Objectives:
This study sought to study the mutual influence of empagliflozin and MRAs in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction).
Methods:
Secondary analysis that compared the effects of empagliflozin versus placebo in 3,730 patients with heart failure and a reduced ejection fraction, of whom 71% used MRAs at randomization.
Results:
The effects of empagliflozin on the primary endpoint, on most efficacy endpoints, and on safety were similar in patients receiving or not receiving an MRA (interaction p > 0.20). For cardiovascular death, the hazard ratios for the effect of empagliflozin versus placebo were 0.82 (95% confidence interval [CI]: 0.65 to 1.05) in MRA users and 1.19 (95% CI: 0.82 to 1.71) in MRA nonusers (interaction p = 0.10); a similar pattern was seen for all-cause mortality (interaction p = 0.098). Among MRA nonusers at baseline, patients in the empagliflozin group were 35% less likely than those in the placebo group to initiate treatment with an MRA following randomization (hazard ratio: 0.65; 95% CI: 0.49 to 0.85). Among MRA users at baseline, patients in the empagliflozin group were 22% less likely than those in the placebo group to discontinue treatment with an MRA following randomization (hazard ratio: 0.78; 95% CI: 0.64 to 0.96). Severe hyperkalemia was less common in the empagliflozin group.
Conclusions:
In EMPEROR-Reduced, the use of MRAs did not influence the effect of empagliflozin to reduce adverse heart failure and renal outcomes. Treatment with empagliflozin was associated with less discontinuation of MRAs. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).
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