HFpEF management – a second kid on the block has emerged

12th September 2024, A/Prof Chee L Khoo

finerenone

We explored the four pillars of treatment for patients with heart failure with reduced ejection fraction (HFrEF) a few years ago now. In patients with heart failure with preserved ejection fraction (HFpEF) however, the options are quite limited. SGLT2 inhibitors is the only class of agents that has been shown to reduce major adverse cardiovascular events (MACE). We also explored the role of the new mineralocorticoid receptor antagonist (MRA), finerenone in reducing composite renal and composite cardiovascular outcomes in patients with diabetic kidney disease (DKD) in the FIDELIO-DKD and FIGARO-DKD trials (1,2). What about the role of finerenone in HFpEF?

Sacubitril with valsartan (Entresto), the only angiotensin receptor neprilysin inhibitor (ARNI), was shown to significantly reduce cardiovascular death and hospitalisation for heart failure (HHF) in patients with HFrEF in the PARADIGM-HF (3). When they tried Entresto on patients with HFpEF in the PARAGON-HF trial, they did not see any statistically significant reduction in cardiovascular mortality nor HHF (4). In the TOPCAT trial, in patients with HFpEF, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure (5). Both dapagliflozin and empagliflozin were shown to significantly reduce HHF and cardiovascular death in patients with HFpEF in DELIVER and EMPA-PRESERVE trials respectively (6,7).

Spironolactone, a steroidal mineralocorticoid receptor antagonist, is increasingly being used in the treatment of hypertension but it comes with a number of common side effects (e.g. gynaecomastia, hyperkalaemia, etc). Finerenone is a nonsteroidal mineralocorticoid receptor antagonist with physiochemical properties that are distinct from spironolactone.

The Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure (FINEARTS-HF) is an international, multi-center, parallel-group, event-driven, double-blind, random controlled trial designed to look at whether finerenone can reduce cardiovascular mortality and HHF in patients with HFpEF (8).

7463 participants aged >40 years with symptomatic heart failure, a left ventricular ejection fraction of 40% or greater, evidence of structural heart disease, and elevated levels of natriuretic peptides. Participants were randomised to receive either a maximum dose of 20 mg or 40 mg finerenone once daily, depending on the baseline eGFR or placebo. The primary outcome was a composite of total worsening heart failure events and death from cardiovascular causes.

Secondary outcomes were tested in a hierarchical order;

  • Total worsening heart failure events
  • Change from baseline in the total symptom score on the Kansas City Cardiomyopathy Questionnaire (KCCQ) at months 6, 9, and 12
  • Improvement in the New York Heart Association (NYHA) functional class at month 12
  • Kidney composite outcome:
    • sustained decrease in the eGFR of ≥50%,
    • sustained decline in the eGFR to <15 ml/min/1.73 m2 of body surface area, or
    • initiation of long-term dialysis or kidney transplantation.

Death from cardiovascular causes and death from any cause were also assessed.

Baseline

Approximately, 50% of the participants had type 2 diabetes. Of the 50% that did not have T2D, 60% of them had prediabetes. At baseline, 84.9% of the patients were being treated with beta-blockers, 35.9% with angiotensin-converting–enzyme inhibitors, 35.0% with angiotensin-receptor blockers, 8.5% with ARNI, and 13.6% with SGLT2 inhibitors. The breakdown in ejection fractions amongst the participants were similar in both groups and were as follows:

EF <50%                              ~36 %

EF 50-60%                          ~44 %

EF >60%                              ~20 %

70% of the participants in both groups were in NYHA Class II while 30% were in NYHA Class III functional class. ~50% of participants had eGFR >60 ml/min/1.73 m2 of body surface area. The mean eGFR was 62 ml/min/1.73 m2 of body surface area. The mean urinary albumin creatinine ratio (uACR) was ~18mg/g. These participants are not your severe CKD patients.

Results

Finerenone resulted in a significantly lower rate of a composite of total worsening heart failure events and death from cardiovascular causes than placebo. Over a median follow-up of 32 months, finerenone significantly reduce the primary outcomes by 16% and significantly reduce total number of worsening heart failure by 18%. The improvement in primary outcomes were consistent across the baseline ventricular ejection fractions and baseline use of SGLT2 inhibitors.

Finerenone was associated with a moderate benefit in patient-reported health status, as measured by the KCCQ total symptom score but not with respect to improvement in the NYHA functional class or the risk of the kidney composite outcome. Finerenone was associated with an increased risk of hyperkalaemia and a reduced risk of hypokalaemia.

The results from the FINEARTS-HF study have given us a second agent in managing our patients with HFpEF. As usual, we await guidelines to get updated and the regulatory bodies to approve the use of finerenone for HFpEF. Finerenone is currently approved under PBS Authority for patients with diabetic kidney disease where the eGFR is > 25 and have urine ACR > 200mg/g. Naturally, this is based on the population of participants in the FIDELIO-DKD and FIGARO-DKD trials. As the FINEARTS-HF population do not have such severe DKD, the criteria for use in patients with HFpEF might not be as strict.

HOT OFF THE PRESS

In further exploratory analysis presented at the Madrid EASD September 10-13, 2024 (which I attended), finerenone was also associated with a 25% reduction in new onset type 2 diabetes (T2D) compared with placebo. Now, finerenone is not known to be an insulin sensitiser and the reduction was unexpected. It was thought that perhaps, when patients feel better with improvement in their heart failure symptoms, they may become more active and this may lead to the reduction in the incidence of T2D.

References:

  1. Bakris GL, Agarwal R, Anker SD, et al; FIDELIO-DKD Investigators. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med. 2020 Dec 3;383(23):2219-2229
  2. Pitt B, Filippatos G, Agarwal R, et al.; FIGARO-DKD Investigators. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med. 2021;385:2252–2263
  3. McMurray JJ, Packer M, Desai AS, et al. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) Eur J Heart Fail. 2013;15:1062–1073.
  4. Jering KS, Zannad F, Claggett B, et al. Cardiovascular and Renal Outcomes of Mineralocorticoid Receptor Antagonist Use in PARAGON-HF. JACC Heart Fail. 2021 Jan;9(1):13-24.
  5. Pitt B, Pfeffer MA, Assmann SF, et al; TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014 Apr 10;370(15):1383-92.
  6. Solomon SD, McMurray JJV, Claggett B, et al; DELIVER Trial Committees and Investigators. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022 Sep 22;387(12):1089-1098.
  7. Anker SD, Butler J, Filippatos G, et al; EMPEROR-Preserved Trial Investigators. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021 Oct 14;385(16):1451-1461
  8. Solomon SD, McMurray JJV, Vaduganathan M, et al; FINEARTS-HF Committees and Investigators. Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2024 Sep 1