Finerenone and Blood Pressure in Heart Failure With Mildly Reduced or Preserved Ejection Fraction

Abstract

This randomized clinical trial analyzes whether finerenone lowers blood pressure and whether its cardiovascular benefits in patients with mildly reduced or preserved ejection fraction heart failure depend on baseline blood pressure or blood-pressure reduction.

Hypertension is observed in approximately 90% of people with heart failure (HF) with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF), and optimal blood pressure (BP) management is a guideline-directed priority of HF management. All guideline-recommended pharmacotherapies for HFpEF treatment have been shown to lower BP, and their benefits on HF progression appear independent of their BP-lowering effects. Whether the same is true for finerenone remains uncertain. In this prespecified secondary analysis of the Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure (FINEARTS-HF) randomized clinical trial, we examined the BP effects of finerenone, and whether baseline BP modified the effect of finerenone on cardiovascular outcomes in HFmrEF/HFpEF.

Methods

The design and findings of FINEARTS-HF have been published. Briefly, FINEARTS-HF evaluated the efficacy and safety of finerenone vs placebo in persons with chronic symptomatic HFmrEF/HFpEF. Exclusion criteria included symptomatic hypotension and uncontrolled systolic BP (≥160 mm Hg if not treated with ≥3 BP-lowering medications or ≥180 mm Hg irrespective of treatment at screening or at randomization). The study protocol (Supplement 1) was approved by ethics committees or institutional review boards at each participating site; all participants provided written informed consent. Randomization is shown in the eFigure in Supplement 2.

Baseline systolic BP was evaluated as a continuous and categorical (<120, 120-129, 130-139, and ≥140 mm Hg) variable. The primary study outcome was a composite of total (first and recurrent) HF events (HF hospitalizations and urgent HF visits) and cardiovascular death. Participants with a recorded baseline systolic BP were included in the analysis. Placebo-adjusted change in systolic BP from baseline to 1 month was assessed using linear regression, adjusting for baseline systolic BP. Overall placebo-adjusted BP effects of finerenone between baseline and 36 months were estimated through a linear mixed-effects model, adjusted for baseline systolic BP, treatment group, and month as fixed effects and including random patient-level intercept terms. The effect of finerenone vs placebo on the primary composite outcome was evaluated according to baseline BP using Poisson regression with restricted cubic splines (3 knots). A causal mediation analysis was performed to estimate the percentage of the overall effect of finerenone (on cardiovascular death and time to first HF event) mediated by the change in systolic BP between baseline and 1 month, using Cox proportional hazards regression models stratified by left ventricular ejection fraction category and geographic region. The proportion of the total effect explained by systolic BP change was estimated, calculating 95% CI via bootstrapping with 500 replications. Selected safety events were evaluated according to baseline systolic BP category. Analyses were conducted using Stata, version 19.5 (StataCorp); 2-sided P values <.05 were considered statistically significant.

Results

Overall, 5999 of 6001 participants had a recorded systolic BP value at baseline and were included in the analysis (mean [SD] age, 72 [10] years; 2732 [45%] female; mean [SD] systolic BP, 129 [15] mm Hg). Compared with placebo, participants treated with finerenone experienced sustained reductions in systolic BP (Figure 1), with most treatment effects observed by 1 month (mean difference, −2.8 mm Hg; 95% CI, −3.4 to −2.1; P < .001). Reductions in systolic BP between baseline and 1 month and over the trial duration were similar irrespective of systolic BP category (Figure 1). Among those who completed treatment (n = 4034), higher final finerenone dose was associated with greater overall placebo-adjusted systolic BP reduction (10 mg: −1.5 mm Hg; 95% CI, −3.4 to 0.3; 20 mg: −3.0 mm Hg; 95% CI, −3.9 to −2.0; 40 mg: −4.0 mm Hg; 95% CI, −4.9 to −3.1; interaction P = .003).

Figure 1. Forest Plot and Line Graph Showing Blood Pressure Effects of Finerenone vs Placebo, Baseline to 36 Months.

A, Overall treatment effect estimate, −3.1 mm Hg; 95% CI, −3.6 to −2.6 mm Hg; P <.001. B, Negative values represent greater blood pressure lowering with finerenone. Placebo-adjusted treatment effects of finerenone for each subgroup were estimated using linear regression adjusting for baseline systolic blood pressure (SBP), including an interaction term for effect modification by baseline SBP category.

^aPlacebo-adjusted treatment effects of finerenone for each subgroup were estimated using a linear mixed-effects model adjusting for baseline SBP, using all available SBP measurements between 1 and 36 months, including an interaction term for effect modification by baseline SBP category.

Finerenone consistently reduced cardiovascular death and total HF events vs placebo, irrespective of baseline systolic and diastolic BP (Figure 2). The systolic BP effects of finerenone did not appear to significantly mediate the benefit of finerenone vs placebo on cardiovascular death and first HF events (percent mediation, 7.4%; 95% CI, −0.7 to 27.0). Serious adverse events (finerenone vs placebo: systolic BP <120 mm Hg, 40% vs 42%; systolic BP 120-<130 mm Hg, 38% vs 37%; systolic BP 130-<140 mm Hg, 38% vs. 40%; systolic BP ≥140 mm Hg, 39% vs 43%; interaction P = .39) and adverse events leading to treatment discontinuation (finerenone vs placebo: systolic BP <120 mm Hg, 4% vs 3%; systolic BP-<130 mm Hg, 3% vs 2%; systolic BP 130-<140 mm Hg, 2% vs 3%; systolic BP ≥140 mm Hg, 4% vs 3%; interaction P = .34) were comparable with finerenone vs placebo irrespective of baseline systolic BP category. Irrespective of assigned treatment, systolic BP <100 mm Hg events were more common with lower vs higher baseline systolic BP (35.2% if baseline systolic BP <120 mm Hg vs 5.7% if baseline systolic BP ≥140 mm Hg). However, relatively higher odds of any systolic BP <100 mm Hg with finerenone vs placebo were not modified by baseline systolic BP category (odds ratio for finerenone vs placebo: 1.6 [95% CI, 1.3-2.0] for systolic BP <120 mm Hg; 1.7 [95% CI, 1.2-2.3] for systolic BP 120-<130 mm Hg; 2.0 [95% CI, 1.4-3.0] for systolic BP 130-<140 mm Hg; 1.9 [95% CI, 1.2-3.0] for systolic BP ≥140 mm Hg; interaction P = .23).

Figure 2. Bar Graphs Showing Treatment Effects of Finerenone on Cardiovascular Death and Total Heart Failure Heart Failure Events.

The figure shows the continuous flexible association between baseline systolic blood pressure (SBP) and diastolic blood pressure (DBP) and treatment effects (95% CI) of finerenone vs placebo, estimated using Poisson regression with a restricted cubic spline (3 knots). The histogram displays the distribution of baseline blood pressure among participants.

Discussion

This FINEARTS-HF analysis provides key insights into the interplay between blood pressure and finerenone in HFmrEF/HFpEF. First, finerenone resulted in early and sustained reductions in systolic BP. Second, finerenone consistently reduced cardiovascular death and HF events irrespective of baseline BP, and these benefits appeared independent of its BP-lowering effects. Third, baseline systolic BP did not appear to modify the safety profile of finerenone.

This analysis has some limitations, including the lack of 24-hour ambulatory BP monitoring and exclusion criteria relating to BP and kidney function, which may limit the generalizability of these findings. In conclusion, this FINEARTS-HF analysis supports the use of finerenone to improve cardiovascular outcomes across a broad BP spectrum in HFmrEF/HFpEF.

Supplement 1.

Trial protocol

Supplement 2.

eFigure. Flow diagram

Supplement 3.

Data sharing statement