Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial

Design

Multicentre, randomized, parallel-group, phase II study, with double-blind placebo and open-label spironolactone comparator arms

N= 393

Objective

To assess the safety and tolerability of BAY 94-8862 (finerenone) in patients with reduced left ventricular ejection fraction (HFrEF) and mild or moderate chronic kidney disease

Study Groups

Finerenone 2.5 mg QD (n= 66)

Finerenone 5 mg QD (n= 67)

Finerenone 10 mg QD (n= 67)

Finerenone 5 mg BID (n= 64)

Spironolactone 25 or 50 mg QD (n= 63)

Placebo (n= 65)

Inclusion Criteria

Age ≥18 years or post-menopausal women aged ≥55 years or women aged ≥18 years not of childbearing potential; diagnosed with chronic heart failure; NYHA class II–III for at least 3 months; stable patients (NYHA class II-III) naive to aldosterone antagonist therapy and stable, low-risk patients (NYHA class II) with ongoing aldosterone antagonist therapy; LVEF ≤40%; known kidney damage for ≥3 months; serum potassium ≤4.8 mmol/L; systolic blood pressure ≥90 mmHg without signs or symptoms of hypotension at the screening visit

Exclusion Criteria

Anuria, acute renal failure, or Addison’s disease; worsening heart failure requiring hospitalization; acute coronary syndrome or unstable coronary artery disease; valvular heart disease; history of hospitalization for hyperkalemia or acute renal failure induced by previous aldosterone antagonist treatment; hepatic insufficiency classified as Child-Pugh B or C; use of any renin inhibitor or aldosterone antagonist in the 30 days before randomization; concomitant therapy with potassium-sparing agents

Methods

Patients were randomized (1:1:1:1:1:1) to receive oral finerenone at doses of 2.5, 5, or 10 mg once daily, or 5 mg BID, placebo, or open-label oral spironolactone, which was given at an initial dose of 25 mg once daily and up-titrated to 50 mg once daily on day 15 ± 1 if serum potassium concentration remained below or equal to 4.8 mmol/L.

Duration

Intervention: 4 weeks

Follow-up: up to 18 weeks

Outcome Measures

Baseline Characteristics

All participants
(N= 393)

Age, years

Male

NYHA functional class

II

III

81.6%

18.4%

Medical history

Ischemic heart disease

Atrial fibrillation

Congestive cardiomyopathy

Arterial hypertension

Diabetes mellitus

64.0%

45.2%

9.2%

66.6%

34.2%

Concomitant medication

Renin-angiotensin system agents

Beta-blockers

Diuretics

94.9%

93.4%

89.0%

Lab values

Serum potassium, mmol/L

Median serum creatinine (range), mg/dL

4.29 ± 0.42

1.4 (0.8 to 3.1)

Results

Endpoint

Finerenone 2.5 mg QD (n= 66)

Spironolactone QD (n= 63) 

Finerenone was associated with:

• Significantly smaller mean increases in serum potassium concentration than spironolactone (0.04–0.30 and 0.45 mmol/L, respectively, p< 0.01)
• Lower incidences of hyperkalemia: 5.3 vs. 12.7%, p= 0.048
• Lower incidence of renal failure: 1.5 vs. 7.9%, p= 0.0153
• Lower incidence of renal impairment: 3.8 vs. 28.6%, p< 0.0001  

Adverse Events

Common Adverse Events: See results

Serious Adverse Events: the highest proportion was in the spironolactone group (5 out of 63 patients; 7.9%).

Percentage that Discontinued due to Adverse Events: the highest proportion occurred in spironolactone group (11 out of 65 patients; 17.5%).

Study Author Conclusions

In patients with HFrEF and moderate CKD, finerenone 5-10 mg/day was at least as effective as spironolactone 25 or 50 mg/day in decreasing biomarkers of hemodynamic stress, but it was associated with lower incidences of hyperkalemia and worsening renal function.

InpharmD Researcher Critique

This was a phase 2 trial of finerenone, and the results are mainly utilized for dose consideration in phase 3 pivotal studies. Only 34% of patients had diabetes, and the incidence of hyperkalemia in diabetic patients who receive finerenone versus spironolactone remains uncertain.

A comparative post hoc analysis of finerenone and spironolactone in resistant hypertension in moderate-to-advanced chronic kidney disease

Design

Post-hoc analysis of two separate trials

N= 919

Objective

To investigate any differences in systolic blood pessure (SBP)-lowering and hyperkalemia risk between finerenone, a nonsteroidal mineralocorticoid receptor antagonists (MRA), and the steroidal MRA spironolactone ± a potassium binder

Study Groups

FIDELITY-TRH

Finerenone (n= 316)

Placebo (n= 308)

AMBER

Spironolactone+patiromer (n= 147)

Spironolactone+placebo (n= 148)

Inclusion Criteria

Exclusion Criteria

Current use of MRAs, history of untreated causes of secondary hypertension other than CKD, use of any investigational product within 30 days or 5 half-lives (whichever is longer) prior to screening, history of malignancy or drug abuse within the past year

Methods

A prespecified subgroup from the FIDELITY study that met the AMBER eligiblity criteria were included for a comparative analysis. The FIDELITY study assessed finerenone vs. placebo in patients with CKD and T2DM while the AMBER study compared spironolactine plus patiromer vs. spironolactone alone.

Duration

FIDELITY: ~17 weeks (120 days) duation

AMBER: 12 weeks duration

Outcome Measures

Changes from baseline to month 4 in office SBP and urinary albumin:creatinine ratio (UACR), hyperkalemia incidences (defined as serum potassium ≥ 5.5 mmol/L), hyperkalemia leading to treatment discontinuation, treatment discontinuation for any reason and other safety events [e.g. hypotension and worsening renal function adverse events (AEs)]

Baseline Characteristics

Finerenone (n= 316)

Spironolactone+placebo (n= 148)

Age, years

Female

Race

White

Black

Other

76%

5%

19%

77%

6%

18%

99%

1%

0

98%

1%

1%

Weight, kg

91

90

82.6

83.5

SBP, mmHg

146

146

143

145

Serum potassium, mmol/L

4.6

4.6

4.7

4.7

Median UACR, mg/g (IQR)

647 (227–1424)

605 (186–1409)

87 (18–467)*

73 (19–400)*

Abbreviations: IQR, interquartile range; SBP, systolic blood pressure; UACR, urine albumin-creatinine ratio

* 24-h UACR

Results

Endpoint

Finerenone (n= 316)

Placebo (n= 308)

p-value

Spironolactone+patiromer (n= 147)

Spironolactone+placebo (n= 148)

LS mean change in office SBP, mmHg

Mean change in UACR, mg/g

Patients with hyperkalemic events

Treatment discontinuation due to hyperkalemia

Abbreviations: LS, least squares

Adverse Events

Serious AEs were reported more frequently in FIDELITY-TRH in both the finerenone (6%) and placebo (5.5%) groups compared with spironolactone+patiromer (0.7%) and spironolactone+placebo (2.7%). Hypotension occurred in 1.6%, 1.0%, 6.1%, and 4.1%, respectively. Worsening renal function occurred in 6.0%, 1.9%, 11.6%, and 9.5%, respectively.

Study Author Conclusions

In patients with TRH and chronic kidney disease compared with spironolactone with or without patiromer, finerenone was associated with a lower SBP reduction and lower risk of hyperkalemia and treatment discontinuation.

InpharmD Researcher Critique