Mineralocorticoid receptor antagonist use does not affect empagliflozin benefit in HFpEF
The benefit of the SGLT2 inhibitor empagliflozin in patients with HF with preserved ejection fraction did not differ between those who did or did not receive mineralocorticoid receptor antagonists, researchers reported.
In a prespecified secondary analysis of the EMPEROR-Preserved trial of patients with HFpEF, researchers found that while the effect of empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) did not vary by MRA use for the primary outcome of CV death and HF hospitalization, the benefit of empagliflozin to reduce first and recurrent HF hospitalizations was more pronounced in mineralocorticoid receptor antagonist (MRA) nonusers.
“Previous studies of SGLT2 inhibitors in patients with HF with reduced ejection fraction suggested that they were effective regardless of MRA therapy and could reduce rates of hyperkalemia and decrease the rate of MRA discontinuation,” João Pedro Ferreira, MD, PhD, assistant professor in the department of physiology and cardiothoracic surgery at the São João Porto Hospital, Portugal, assistant professor at the University of Lorraine in the Centre for Clinical and Plurithematic Investigation, Nancy, France, and research fellow at the University of Glasgow, U.K., and colleagues wrote in the study background. “Therefore, it is important to also assess the influence of background MRA use on the efficacy and safety of empagliflozin in patients with HFpEF.”
Use of MRAs at baseline
Ferreira and colleagues assessed the influence of MRA use at baseline on the efficacy of empagliflozin, whether empagliflozin influenced the prescribing of MRAs and rates of hyperkalemia after randomization.
Ferreira and colleagues compared the effects of empagliflozin vs. placebo among 2,244 MRA users and 3,744 nonusers at baseline with treatment-by-MRA use interaction terms.
Participants prescribed an MRA at baseline experienced higher event rates than MRA nonusers, with a placebo group primary outcome of 9.4 vs. 8.2 events per 100 person-years.
“MRA use was higher in those with a more congested clinical picture, with more hospitalizations for HF within the past 12 months, worse HF symptoms, mildly reduced ejection fractions, higher NT-proBNP levels, and more use of loop diuretic agents,” the researchers wrote. “These findings indicate more advanced HF presentation among MRA users, which is supported by the higher placebo event rates seen in this subgroup.”
The benefit of empagliflozin to reduce the primary outcome of CV death or HF hospitalization was not significantly different between groups, with an HR of 0.73 for MRA nonusers (95% CI, 0.62-0.87) and an HR of 0.87 for MRA users (95% CI, 0.71-1.06; P = .22 for interaction).
The effect of empagliflozin to reduce first and recurrent HF hospitalizations was more pronounced in MRA nonusers than in MRA users; with HRs of 0.6 (95% CI, 0.47-0.77) and 0.9 (95% CI, 0.68-1.19), respectively (P = .038 for interaction).
MRA users experienced almost twice as many hyperkalemia events as MRA nonusers; empagliflozin reduced risk for hyperkalemia or initiation of potassium binders regardless of MRA use, according to the researchers.
Assessing between-group differences
The researchers noted that the differences in symptom severity, natriuretic peptide levels, recent HF hospitalization, NYHA functional class, loop diuretic use and volume overload between MRA users vs. nonusers suggests MRA users were more congestive, which may have influenced the observed treatment effect differences.
“Although it is possible to hypothesize that MRA and empagliflozin might have limited additive effects, this seems unlikely, as empagliflozin reduced major HF outcomes in the EMPEROR-Reduced trial, in which more than 70% of patients were using MRAs at baseline and the effect appeared to be more pronounced among MRA users,” the researchers wrote. “Still, it should be noted that in EMPEROR-Preserved, the difference in treatment effect in total HF hospitalizations between MRA users and nonusers was seen particularly in the subgroup of patients with left ventricular EF of at least 50%, but not among those with LVEFs between 41% and 49% in whom the treatment effect was more homogeneous.”
As Healio previously reported, data published in the Journal of the American College of Cardiology in March 2021 showed MRA use in the EMPEROR-Reduced trial did not influence the ability of empagliflozin to reduce adverse HF and renal outcomes. In that study, the effect of empagliflozin compared with placebo for CV death trended toward being more beneficial in patients using MRAs than in patients not using them. Researchers observed a similar trend for all-cause mortality.
Collapse