Efficacy and Safety of Finerenone Across the Ejection Fraction Spectrum in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Analysis of the FINEARTS-HF Trial

Abstract

BACKGROUND:

The effects of treatments for heart failure (HF) may vary among patients according to left ventricular ejection fraction (LVEF). In FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure), the nonsteroidal mineralocorticoid receptor antagonist finerenone reduced the risk of cardiovascular death and total worsening HF events in patients with HF with mildly reduced or preserved ejection fraction. We examined the effect of finerenone according to LVEF in FINEARTS-HF.

METHODS:

FINEARTS-HF was a randomized, placebo-controlled trial examining the efficacy and safety of finerenone in patients with HF and LVEF ≥40%. The treatment effect of finerenone was examined in prespecified analyses according to LVEF categories (<50%, ≥50% to <60%, and ≥60%) and with LVEF as a continuous variable. The primary outcome was a composite of total (first and recurrent) worsening HF events and cardiovascular death.

RESULTS:

Baseline LVEF data were available for 5993 of the 6001 participants in FINEARTS-HF. Mean and median LVEF were 53±8% and 53% (interquartile range, 46%–58%), respectively. LVEF was <50% in 2172 (36%), between 50% and <60% in 2674 (45%), and ≥60% in 1147 (19%). Patients with higher LVEF were older, were more commonly female, were less likely to have a history of coronary artery disease, and more frequently had a history of hypertension and chronic kidney disease compared with those with a lower LVEF. Finerenone reduced the risk of cardiovascular death and total HF events consistently across LVEF categories (LVEF <50% rate ratio, 0.84 [95% CI, 0.68–1.03]; LVEF ≥50% to <60% rate ratio, 0.80 [0.66–0.97]; and LVEF ≥60% rate ratio, 0.94 [0.70–1.25]; P_interaction=0.70). There was no modification of the benefit of finerenone across the range of LVEF when analyzed as a continuous variable (P_interaction=0.28). There was a similar consistent effect of finerenone on reducing the total number of worsening HF events (continuous P_interaction=0.26).

CONCLUSIONS:

In patients with HF with mildly reduced or preserved ejection fraction, finerenone reduced the risk of cardiovascular death and worsening HF events, irrespective of LVEF.

REGISTRATION:

URL: https://www.clinicaltrials.gov; Unique identifier: NCT04435626. URL: https://eudract.ema.europa.eu; Unique identifier: 2020-000306-29.

Clinical Perspective.

What Is New?

• Previous post hoc analyses of randomized clinical trials in patients with heart failure with mildly reduced or preserved ejection fraction have suggested that the benefits of neurohumoral modulating therapies are attenuated or absent at higher left ventricular ejection fraction.

• In this prespecified analysis of FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure), the nonsteroidal mineralocorticoid receptor antagonist finerenone reduced the risk of cardiovascular death and worsening heart failure events consistently across the entire range of left ventricular ejection fraction in patients with heart failure with mildly reduced or preserved ejection fraction.

What Are the Clinical Implications?

• These data support that finerenone should be considered as a foundational treatment for heart failure with mildly reduced or preserved ejection fraction, regardless of left ventricular ejection fraction.

The clinical characteristics and the risk of outcomes vary substantially among patients with heart failure (HF) according to left ventricular ejection fraction (LVEF).^1,2 Furthermore, the efficacy of several treatments for heart failure differs across the range of LVEF. The benefits of some neurohumoral modulating therapies on reducing the risk of death and worsening HF in patients with HF with reduced ejection fraction were not replicated in trials of patients with HF with mildly reduced ejection fraction (HFmrEF) or HF with preserved ejection fraction (HFpEF).^3–7 However, a series of post hoc analyses from randomized, placebo-controlled trials pooling individual patient data from across the entire range of LVEF have shown that the benefits of some neurohumoral modulating treatments may extend to those with a LVEF reduced below the normal range (ie, <55%–60%), with attenuation or absence of benefit in those with a normal LVEF.^8–10 Conversely, the benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2i) were consistent across the entire spectrum of LVEF.^11,12 Therefore, it is important to understand whether the efficacy of new treatments for patients with HFmrEF or HFpEF is modified by LVEF.

In FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure), the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone reduced the risk of cardiovascular death and worsening HF events in patients with HF and an LVEF ≥40%.^13–15 This analysis examined whether the benefits and safety of finerenone differed across the range of LVEF among patients with HFmrEF and HFpEF enrolled in FINEARTS-HF.

METHODS

FINEARTS-HF was a prospective, randomized, double-blind, placebo-controlled, event-driven trial that examined the efficacy and safety of finerenone compared with placebo in patients with HFmrEF or HFpEF. The design, baseline characteristics, and primary results have been published.^13–15 Ethics committees of the 653 participating institutions in 37 countries approved the protocol and all patients gave written consent.

Study Patients and Treatment

Key inclusion criteria were age ≥40 years, symptomatic HF in New York Heart Association (NYHA) functional class II through IV, treatment with a diuretic for ≥30 days before randomization, and LVEF ≥40% with evidence of structural heart disease (left atrial enlargement or left ventricular hypertrophy) measured within 12 months of screening. Patients were also required to have elevated natriuretic peptide levels (NT-proBNP [N-terminal pro–B-type natriuretic peptide] ≥300 pg/mL [or BNP (B-type natriuretic peptide) ≥100 pg/mL] for patients in sinus rhythm or NT-proBNP ≥900 pg/mL [or BNP ≥300 pg/mL] for patients in atrial fibrillation) measured within 90 days in those with a recent worsening HF event within 90 days of randomization or measured 30 days before randomization in those without a recent worsening HF event. Both ambulatory and hospitalized patients were eligible for enrollment. Patients with previous LVEF <40% with subsequent improvement to ≥40% were also eligible for enrollment provided that ongoing HF symptoms were present and all other inclusion criteria were satisfied. Key exclusion criteria were estimated glomerular filtration rate (eGFR) <25 mL·min·1.73 m², serum/plasma potassium >5.0 mmol/L at screening or randomization, or symptomatic hypotension with mean systolic blood pressure <90 mm Hg at screening or randomization. A complete list of exclusion criteria is provided in the design article.¹³

Eligible participants were randomized in a 1:1 ratio to finerenone or matching placebo. The starting dose was 10 mg once daily in participants with an eGFR ≤60 mL·min·1.73 m² with a maximum maintenance dose of 20 mg once daily, whereas the starting dose was 20 mg once daily if the eGFR was >60 mL·min·1.73 m² with a maximum maintenance dose of 40 mg once daily.

Ejection Fraction

Investigators were asked to record a patient’s LVEF on the electronic case report form using the most recent measurement recorded within 12 months of screening. An LVEF was available in 5993 of 6001 patients (>99%) at baseline. For the purposes of this analysis, LVEF was analyzed in groups (<50%, ≥50%–<60%, and ≥60%) and as a continuous variable. In a sensitivity analysis, LVEF was analyzed in groups according to LVEF <50%, ≥50% to <60%, ≥60% to <70%, and ≥70%.

Outcomes

The primary trial outcome was the composite of total (first and recurrent) HF events (ie, HF hospitalization or urgent HF visit) and cardiovascular death. Prespecified secondary outcomes were the total number of HF events; improvement in NYHA class from baseline to 12 months; change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score from baseline to 6, 9, and 12 months; a composite kidney end point (defined as a sustained decline in eGFR ≥50% relative to baseline over at least 4 weeks, or sustained eGFR decline <15 mL·min·1.73 m², or initiation of dialysis or renal transplantation); and all-cause death. All deaths and potential primary outcome nonfatal events were adjudicated by an independent blinded committee.

Prespecified safety analyses included adverse events leading to discontinuation of trial treatment and adverse events of interest (ie, elevations in serum creatinine, hyperkalemia, hypokalemia, and hypotension). Safety analyses were performed in patients who had undergone randomization and received at least one dose of finerenone or placebo (a total of 15 randomized patients were excluded from the safety analysis).

Statistical Analysis

Baseline characteristics are summarized according to LVEF groups as frequencies with percentages for categorical variables and means with standard deviations or medians with interquartile ranges for continuous variables. Differences across LVEF categories were compared by the Jonckheere-Terpstra trend test for continuous variables and the Cochran-Armitage trend test for categorical variables.

The crude incidence rates for each outcome of interest across the range of LVEF are presented per 100 patient-years of follow-up and are presented graphically using a Poisson regression model with LVEF included as a continuous variable using restricted cubic splines with 3 knots placed at the 10th, 50th, and 90th quantiles. The association between LVEF and clinical outcomes was evaluated using semiparametric proportional-rates models for total (first and recurrent) events and Cox proportional hazards models for time to first event data, stratified according to geographic region.¹⁶ Further adjustment was performed for age, sex, eGFR, NYHA functional class, heart rate, systolic blood pressure, body mass index, (log)NT-proBNP, and history of type 2 diabetes, previous HF hospitalization, atrial fibrillation, and myocardial infarction.

The effect of finerenone compared with placebo was calculated as a rate ratio (RR) and 95% CI derived from semiparametric proportional rates models for total (first and recurrent) events or as a hazard ratio (HR) and 95% CI from Cox proportional hazards models for time to first events.¹⁶ All models were stratified by geographic region as prespecified in the statistical analysis plan for the main trial.¹⁵ These analyses were repeated with adjustment for the same variables described previously. The effect of finerenone on outcomes according to LVEF was examined with LVEF as a continuous variable modeled as a spline with 3 knots placed at the 10th, 50th, and 90th quantiles. The interaction between LVEF (as a spline with the same knots) and treatment was tested in the model. In the context of finding no treatment effect modification by baseline LVEF, the absolute benefit of finerenone on the primary outcome was calculated by modeling a consistent treatment effect across the range of baseline LVEF. The absolute rate difference was calculated using a Poisson regression model with LVEF included as a continuous variable using a restricted cubic spline with 3 knots placed at the 10th, 50th, and 90th quantiles. The proportion of patients with improvement in NYHA class from baseline to 12 months was analyzed using a logistic regression model, adjusted for geographic region. The change in KCCQ Total Symptom Score from baseline to 12 months was analyzed using a linear regression model, adjusted for baseline value and geographic region. Safety outcomes are reported as counts and percentages according to randomized treatment. Logistic regression was used with a treatment-by-LVEF category interaction term to examine the presence of any modification of treatment effect according to LVEF.

All analyses were performed using Stata version 18. P<0.05 was considered nominally statistically significant. Trial data will be made available by the sponsor, Bayer, in accordance with its data-sharing policy.

RESULTS

LVEF was recorded in 5993 of the 6001 participants in FINEARTS-HF. The mean±SD and median (interquartile range) LVEF at baseline were 53±8% and 53% (46%–58%), respectively, with a range of 34% to 84%. The distribution of LVEF is displayed in Figure 1. LVEF was <50% in 2172 (36%), between 50% and <60% in 2674 (45%), and ≥60% in 1147 (19%). Baseline characteristics according to LVEF group are detailed in Table 1 and Table S1. Compared with those with a lower LVEF, patients with a higher LVEF were older, were more commonly female, had lower (ie, worse) KCCQ Total Symptom Score values, had higher mean body mass index and systolic blood pressure, and had a greater prevalence of kidney dysfunction. Patients with a lower LVEF were more likely to have a history of myocardial infarction or a previous HF hospitalization, had higher NT-proBNP concentrations, and were more likely to be treated with a β-blocker, renin-angiotensin system inhibitor, angiotensin receptor-neprilysin inhibitor, SGLT2 inhibitor, or a loop diuretic than those with a higher LVEF. A history of previous LVEF <40% was most common in those with a baseline LVEF <50% compared with those with a higher LVEF.

Figure 1.

Distribution of baseline left ventricular ejection fraction. LVEF indicates baseline left ventricular ejection fraction.

Table 1.

Baseline Characteristics According to Baseline Left Ventricular Ejection Fraction Group

Outcomes According to LVEF

The crude incidence of outcomes according to baseline LVEF are displayed as a continuous variable in Figure 2 and by LVEF category in Table 2. The rates of the primary composite outcome (cardiovascular death and the total number of worsening HF events), its individual components, and all-cause mortality were highest in patients with lower LVEF, with rates decreasing across the range of LVEF 40% to 60%, with a plateauing of event rates in patients with LVEF ≥60%.

Figure 2.

Incidence of outcomes across the spectrum of left ventricular ejection fraction. The crude incidence rate of outcomes per 100 patient-years was calculated using a Poisson regression model with left ventricular ejection fraction (LVEF) included as a continuous variable using restricted cubic splines with 3 knots. HF indicates heart failure.

Table 2.

Risk of Outcomes According to Baseline Left Ventricular Ejection Fraction Group

After adjustment for baseline covariates, the rate of the primary composite outcome was similar across LVEF categories: RR, 1.07 (95% CI, 0.89–1.29) for LVEF <50% and 1.09 (95% CI, 0.91–1.31) for LVEF ≥50% to <60% (referent group=LVEF ≥60%; Table 2). Similar results were seen for the individual components of the primary composite outcome in both total and time to first event analyses, the composite kidney outcome, and all-cause mortality.

Treatment Effect of Finerenone According to LVEF

The treatment effect of finerenone compared with placebo on outcomes is detailed by LVEF groups in Table 3 and with LVEF analyzed as a continuous variable in Figure 3. The effect of finerenone on reducing the risk of the primary composite outcome of cardiovascular death and the total number of worsening HF events was not modified by LVEF when analyzed in categories (P_interaction=0.70) or as a continuous variable (P_interaction=0.28). In a continuous spline model (Figure 3), the RR estimate for the primary composite outcome was <1.0, indicating a benefit of finerenone, from an LVEF of 40% up to ≈70%, with a substantial widening of the 95% CI at higher LVEF values of >70%. The HR for finerenone compared with placebo for the time to first event outcome of cardiovascular death or first worsening HF event was <1.0 across the whole range of LVEFs studied (P_interaction=0.62). The absolute benefit of finerenone compared with placebo on the primary composite outcome was consistent when expressed as a rate difference across the range of LVEF, as displayed in Figure 4.

Table 3.

Effect of Randomized Treatment on Outcomes According to Baseline Left Ventricular Ejection Fraction Group

Figure 3.

Treatment effect of finerenone compared with placebo across the spectrum of left ventricular ejection fraction. The effect of finerenone on outcomes according to left ventricular ejection fraction (LVEF) analyzed as a continuous variable was examined with an LVEF by treatment interaction with LVEF modeled as a spline with 3 knots at the 10th, 50th, and 90th quantiles. For total (first and recurrent) event outcomes, rate ratios and 95% CIs were estimated using the semiparametric proportional rates method of Lin et al¹⁶ stratified according to geographic region. For time to first event outcomes, hazard ratios and 95% CIs were estimated using Cox regression models, stratified by geographic region. An effect estimate of <1.0 indicates benefit of finerenone. Shaded areas represent 95% CIs. P_interaction represents the interaction between LVEF as a continuous variable and treatment. HF indicates heart failure.

Figure 4.

Absolute benefit of finerenone compared with placebo across the spectrum of left ventricular ejection fraction. The absolute benefit of finerenone on the primary outcome was calculated by modeling a consistent treatment effect across the range of baseline left ventricular ejection fraction (LVEF). The absolute rate difference was calculated using a Poisson regression model with LVEF included as a continuous variable using a restricted cubic spline with 3 knots. HF indicates heart failure.

There was no statistically significant interaction between LVEF and the effect of finerenone on reducing the number of total worsening HF events (categorical P_interaction=0.67 and continuous P_interaction=0.26; Table 3). In the continuous spline analysis, a similar pattern to the primary outcome was observed for the total number of worsening HF events, with the RR estimate being <1.0 for the majority of the LVEF range (P_interaction=0.26; Figure 3). Again similarly to the primary outcome, when considered as a time to first event outcome, the HR estimate was indicative of a benefit of finerenone (ie, remained <1.0) across the whole LVEF range studied (P_interaction=0.85).

The effect of finerenone was consistent across the range of LVEF on all other outcomes examined (Table 3; Figure 3) except for the kidney composite outcome. In those with an LVEF ≥60%, there was an apparent benefit of finerenone on the kidney outcome, whereas there were more kidney-related events in those randomized to finerenone as compared with placebo in the lower LVEF groups (categorical P_interaction=0.003 and continuous P_interaction=0.15). Finerenone had a consistent benefit on increasing the KCCQ Total Symptom Score from baseline to month 12 across the range of LVEF.

In sensitivity analyses, results were consistent after adjustment for baseline covariates (Table 3) and when LVEF was categorized into <50%, ≥50% to <60%, ≥60% to <70%, and ≥70% (Table S2).

Safety Outcomes According to LVEF

The occurrence of safety outcomes of interest according to randomized treatment and LVEF category are detailed in Table 4. Patients randomized to finerenone had more frequent increases in serum creatinine and potassium than the placebo group, and this did not differ significantly across LVEF groups.

Table 4.

Safety Outcomes According to Randomized Treatment and Baseline Left Ventricular Ejection Fraction Group

DISCUSSION

In FINEARTS-HF, the beneficial effect of finerenone on reducing the risk of cardiovascular death and the total number of HF hospitalizations was consistent across the range of LVEF in patients with HF and an LVEF ≥40%. These data support the use of finerenone as a foundational therapy for patients with HFmrEF or HFpEF, along with an SGLT2i.

Consistent with previous trials, we observed substantial heterogeneity according to LVEF in the clinical characteristics of patients with HFmrEF and HFpEF enrolled in FINEARTS-HF.^1,2 Patients with a lower LVEF in the HFmrEF range had several features resembling a “HF with reduced ejection fraction–like” phenotype; they were more likely to be men, had a greater prevalence of coronary artery disease, and were more frequently prescribed beta-blockers and renin-angiotensin receptor antagonists (either alone or in combination with a neprilysin inhibitor). Despite evidence of benefit in HF regardless of LVEF, the use of SGLT2i was more common in those with a lower ejection fraction, probably reflecting the later approval of the use of these drugs in HFmrEF or HFpEF, which occurred during follow-up of FINEARTS-HF. Patients with a higher LVEF were older, were more often women, and had less ischemic heart disease, but a greater prevalence of hypertension, higher body mass index, and lower eGFR. Natriuretic peptide concentrations were lower with increasing LVEF.

The crude rate of outcomes was highest in patients with the lowest LVEF in the HFmrEF range, with a plateauing of event rates for all outcomes above an LVEF of 50%. This is consistent with previous reports showing that patients with HFmrEF have intermediate event rates compared with patients with HF with reduced ejection fraction, in whom there is a linear inverse relationship between LVEF and a higher risk of adverse outcomes, and those with HFpEF.^1,2,8–11 In HFpEF, event rates were generally consistent across the range of LVEF ≥50%. After adjustment for baseline covariates, including NT-proBNP, we did not observe any significant between-LVEF category differences in the adjusted risk of outcomes.

FINEARTS-HF is the first trial to show that a drug targeting a neurohumoral pathway can reduce morbidity and mortality rates, as well as improve symptoms, in patients with HFmrEF or HFpEF. Previous trials in patients with HFmrEF or HFpEF did not show a clear benefit of renin-angiotensin system inhibition or the combined angiotensin receptor-neprilysin inhibitor sacubitril/valsartan.^3–5,7 In TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function; URL: https://www.clinicaltrials.gov; Unique identifier: NCT00094302), the steroidal MRA spironolactone did not reduce the risk of the primary end point of cardiovascular death, HF hospitalization, or resuscitated cardiac arrest in the overall trial population of patients with LVEF ≥45%.⁶ However, in a post hoc analysis of TOPCAT according to LVEF, spironolactone improved outcomes in patients with a reduced LVEF in the mildly reduced range, but not in those with an LVEF in the normal range (ie, >55%–60%).⁸ Similar findings of a varying treatment effect according to LVEF were seen with the angiotensin receptor blocker candesartan in the CHARM program (Candesartan Cilexetil in Heart Failure Assessment of Reduction in Mortality and Morbidity) and with sacubitril/valsartan in PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction; URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711), which enrolled patients with an LVEF ≥45%, although none of these findings was definitive, and all of these inferences were based on post hoc exploratory analyses.^9,10

Although the benefits of finerenone on the primary composite outcome and the total number of worsening HF events appeared to be attenuated in patients with an LVEF >70% on visual assessment of the continuous spline analysis, the overall tests for heterogeneity of treatment effect were nonsignificant in both continuous and categorical analyses. The relatively small number of patients with an LVEF >70% and few events (41 primary outcome events in 23 of 108 patients with LVEF >70% [1.8% of patients and 2% of the total number of events in those with LVEF data]) may have limited the certainty in the treatment effect on recurrent event outcomes at higher LVEF values, as indicated by the relatively wide 95% CI. Ongoing trials with finerenone in similar patient populations will provide more data to help clarify this uncertainty (CONFIRMATION-HF [A Study to Determine the Efficacy and Safety of Finerenone and SGLT2i in Combination in Hospitalized Patients With Heart Failure]; URL: https://www.clinicaltrials.gov; Unique identifier: NCT06024746; and REDEFINE-HF [A Study to Determine the Efficacy and Safety of Finerenone on Morbidity and Mortality Among Hospitalized Heart Failure Patients]; URL: https://www.clinicaltrials.gov; Unique identifier: NCT06008197). Although there appeared to be an interaction between the effect of finerenone on the kidney outcome and baseline LVEF category, the improbably low hazard ratio in the LVEF ≥60% group probably reflects the play of chance due to the small number of kidney end points overall (n=130) and in this subgroup (n=27). Likewise, the apparent interaction between finerenone-related hyperkalemia and LVEF is likely to be spurious for similar reasons (with only 17 events in the LVEF >60% group).

Why might the consistency of the benefit of finerenone across the LVEF range in HFmrEF and HFpEF be different from the previously observed attenuation of the effect of other neurohumoral modulating treatments at higher LVEF values? The first potential explanation is that finerenone has a specific mechanism (or mechanisms) of action and properties that distinguish it from other treatments and underlie its clinical benefits across the spectrum of LVEF in HFmrEF and HFpEF. Finerenone is a nonsteroidal MRA that is thought to have greater selectivity and binding affinity for the mineralocorticoid receptor along with a more balanced tissue distribution between the heart and kidney than eplerenone or spironolactone.^17,18 There are few direct comparisons between finerenone and other MRAs in patients with HF. In ARTS-HF (Mineralocorticoid Receptor Antagonist Tolerability Study–Heart Failure; URL: https://www.clinicaltrials.gov; Unique identifier: NCT01807221), finerenone had a similar effect to eplerenone on the proportion of patients with a >30% decrease in NT-proBNP.¹⁹ There was a suggestion of a greater benefit of finerenone on an exploratory clinical composite outcome; however, this trial was not powered for between-treatment comparisons on clinical outcomes.

The second potential explanation may be that patients with a higher LVEF enrolled in FINEARTS-HF were different from those in previous trials and may have had characteristics that made them more likely to benefit from an MRA. One notable difference in FINEARTS-HF was that NT-proBNP concentrations in patients with an LVEF ≥60% were higher than those in other comparative HFmrEF/HFpEF trials. In a pooled analysis of 4 large HFmrEF/HFpEF trials, the median NT-proBNP level in patients with an LVEF ≥60% was ≈375 pg/mL and 1470 pg/mL in patients with sinus rhythm and atrial fibrillation, respectively.² The corresponding values in FINEARTS-HF were 531 pg/mL and 1697 pg/mL. One of the reasons suggested for the apparent diminution of the effect of neurohumoral modulation with increasing LVEF is that the degree of neurohumoral activation is less in patients with higher LVEF compared with lower values.²⁰ In FINEARTS-HF, the relatively higher NT-proBNP concentrations in patients with a higher LVEF may reflect a greater degree of neurohumoral activation. Patients therefore may have stood to gain more from antagonizing aldosterone’s activation of the mineralocorticoid receptor. Against this hypothesis, however, is the absence of any treatment effect modification by baseline NT-proBNP level in the prespecified subgroup of less than or equal to, or greater than, the median baseline value.¹⁵ Another potential contributing factor to the relatively higher NT-proBNP concentrations in patients with LVEF ≥60% may have been the high proportion of patients (42%) randomized during or within 3 months of a worsening HF event in this subgroup. In PARAGON-HF, patients with HFmrEF or HFpEF with a more recent episode of worsening HF appeared to benefit from sacubitril/valsartan, with no benefit in those without a history of HF hospitalization.²¹ There was a similar suggestion of a trend to a greater benefit of finerenone in those with a more recent worsening HF event in FINEARTS-HF.¹⁵

Collagen deposition and myocardial fibrosis are key pathogenic processes in the development and progression of HFpEF and inhibition of aldosterone-mediated myocardial fibrosis is one of the key mechanisms of action of an MRA.^22–25 In a substudy of RALES (Randomized Aldactone Evaluation Study), the benefits of spironolactone on outcomes in patients with HF with reduced ejection fraction were more pronounced in patients with higher levels of circulating biomarkers reflective of collagen deposition.²⁴ The finding of a benefit of finerenone across the whole range of LVEF, and particularly in those with a higher LVEF (with a greater prevalence of hypertension, which is associated with myocardial fibrosis), may reflect the presence of profibrotic activity that is modifiable by finerenone across the range of LVEF studied. The greater selectivity of finerenone for the mineralocorticoid receptor and better cardiac tissue distribution compared with spironolactone may explain, in part, the benefits of finerenone at higher LVEF values that were not seen in TOPCAT.^8,17 Future biomarker analyses may provide further mechanistic insight into the benefits of finerenone in patients with HFmrEF and HFpEF.

There is increasing awareness of the prevalence of amyloid cardiomyopathy among patients with HFpEF, particularly among those with a higher LVEF. This, along with a specific amyloid cardiomyopathy exclusion criterion, may have led to fewer patients being included in FINEARTS-HF with undiagnosed amyloid cardiomyopathy compared with previous trials.¹³ The inclusion of these patients in previous trials may have contributed to the absence of benefit of neurohumoral modulating treatments at higher LVEF values. The relative absence of patients with undiagnosed amyloid cardiomyopathy in FINEARTS-HF may have resulted in more patients with a higher LVEF who were more likely to benefit from aldosterone antagonism.

There are limitations of this analysis. LVEF values were investigator-reported and were not verified by a core laboratory. Furthermore, an LVEF value could be used for eligibility if recorded within the 12 months before randomization, so was not necessarily contemporary to the time of randomization. Patients in FINEARTS-HF were required to have elevated levels of natriuretic peptides to be eligible for randomization; therefore, we are unable to comment on the efficacy of finerenone across the spectrum of LVEF in patients with HFmrEF or HFpEF with low or normal NT-proBNP levels.

Conclusions

In the randomized, placebo-controlled FINEARTS-HF trial, the nonsteroidal MRA finerenone reduced the risk of cardiovascular death and worsening HF events consistently across the range of LVEF in patients with HFmrEF or HFpEF.

ARTICLE INFORMATION

Sources of Funding

FINEARTS-HF was funded by Bayer. Drs McMurray and Jhund were supported by a British Heart Foundation Centre of Research Excellence grant RE/18/6/34217 and the Vera Melrose Heart Failure Research Fund.

Disclosures

Dr Docherty reports that his employer, the University of Glasgow, has been remunerated by AstraZeneca for his work on clinical trials, and he has received speaker fees from AstraZeneca, Boehringer Ingelheim, Pharmacosomos, and Translational Medicine Academy; has served on advisory boards or performed consultancy for FIRE-1, Us2.ai, and Bayer AG; holds stock in Us2.ai; has served on a Clinical Endpoint Committee for Bayer AG; and has received research grant support (paid to his institution) from AstraZeneca, Roche, Novartis, and Boehringer Ingelheim. Dr Jhund reports speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, and Sun Pharmaceuticals; advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; and research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc, and Roche Diagnostics. Dr Jhund is Director of GCTP Ltd. Dr Jhund’s employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk. Dr Claggett has received personal consulting fees from Alnylam, Bristol Myers Squibb, Cardior, Cardurion, Corvia, CVRx, Eli Lilly, Intellia, and Rocket, and has served on a data safety monitoring board for Novo Nordisk. Dr Desai has received institutional research grants (to Brigham and Women’s Hospital) from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and Pfizer, as well as personal consulting fees from Abbott, Alnylam, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Medpace, Medtronic, Merck, Novartis, Parexel, Porter Health, Regeneron, River2Renal, Roche, Veristat, Verily, and Zydus. K. Mueller and Drs Viswanathan and Scalise are employees of Bayer. Dr Lam has received research support from Novo Nordisk and Roche Diagnostics; has received consulting fees from Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and is a cofounder and nonexecutive director of Us2.ai. Dr Senni has served on advisory boards, performed consultancy, and received honoraria for Novartis, Abbott, Merck, MSD, Vifor, AstraZeneca, Cardurion, Novo Nordisk, Bayer, and Boehringer Ingelheim. Dr Shah has received research grants from the National Institutes of Health (U54 HL160273, X01 HL169712, R01 HL140731, R01 HL149423), American Heart Association (24SFRNPCN1291224), AstraZeneca, Corvia, and Pfizer, and consulting fees from Abbott, Alleviant, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. Dr Voors’ employer received consultancy fees or research support from Adrenomed, Anacardio, AstraZeneca, Bayer AG, BMS, Boehringer Ingelheim, Corteria, Eli Lilly, Merck, Moderna, Novartis, Novo Nordisk, Roche Diagnostics, and SalubrisBio. Dr Zannad reports personal fees from 89Bio, Abbott, Acceleron, Applied Therapeutics, Bayer, Betagenon, Boehringer, BMS, CVRx, Cambrian, Cardior, Cereno pharmaceutical, Cellprothera, CEVA, Inventiva, KBP, Merck, NovoNordisk, Owkin, Otsuka, Roche Diagnostics, Northsea, and USa2; having stock options at G3Pharmaceutical and equities at Cereno, Cardiorenal, and Eshmoun Clinical Research; and being the founder of Cardiovascular Clinical Trialists. Dr Pitt is a consultant for Bayer, AstraZeneca, Boehringer Ingelheim, Lexicon, Bristol Meyers Squibb, KBP Biosciences (stock or stock options), Sarfez Pharmaceuticals (stock or stock options), SQinnovations (stock or stock options), G3 Pharmaceuticals, Sea Star Medical (stock or stock options), Vifor (stock or stock options), Prointel (stock or stock options), and Brainstorm Medical (stock or stock options); US patent 9931412 (site-specific delivery of eplerenone to the myocardium); and US patent pending 63/045,783 (histone modulating agents for the prevention and treatment of organ failure). Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, BMS, Boehringer Ingelheim, Chiesi, Cytokinetics, Fresenius Medical Care, Idorsia Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Milestone Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health, and participates on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Solomon has received research grants from Alexion, Alnylam, AstraZeneca, Bellerophon, Bayer, BMS, Boston Scientific, Cytokinetics, Edgewise, Eidos, Gossamer, GSK, Ionis, Lilly, MyoKardia, NIH/NHLBI, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.ai, and has consulted for Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, MyoKardia, Novartis, Roche, Theracos, Quantum Genomics, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo. Dr McMurray reports payments through Glasgow University from work on clinical trials, consulting, and grants from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, Novartis, British Heart Foundation, National Institutes of Health–National Heart, Lung, and Blood Institute, Boehringer Ingelheim, SQ Innovations, and Catalyze Group; personal consultancy fees from Alynylam Pharmaceuticals, Amgen, AnaCardio, AstraZeneca, Bayer, Berlin Cures, BMS, Cardurion, Cytokinetics, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, and River 2 Renal Corp; and personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals & Pharmaceuticals Ltd, Lupin Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, and Sun Pharmaceuticals.

Supplemental Material

Tables S1 and S2

Supplementary Material

cir-151-45-s002.pdf ^{(224.5KB, pdf)}