Cardiovascular and kidney outcomes-Nursing Case Study
Abstract
Aims
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Cardiovascular and kidney outcomes remain inspected in distinct overlapping stages of CKD by the collective studies FIDELIO-DKD and FIGARO-DKD in patients with type 2 diabetes and chronic kidney disease (CKD). The intention of the FIDELITY analysis remains to carry out a sole patient-level, above a joint efficacy and safety analysis beyond a broad spectrum of CKD for the provision of a more vigorous rate of the benefit and safety of finer enone in contrast with placebo (Cardiovascular and kidney outcomes-Nursing Case Study).
Methods and results
For this default analysis, two phases III, multi-center, double-blind trials involving patients with CKD and type 2 diabetes, recombined 1:1 to finer enone or placebo, were merged. Main time-to-event significant outcomes were a combination of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure, and a composite of kidney failure, a sustained ≥57% decrease in estimated glomerular filtration rate from baseline over ≥4 weeks, or renal death (Cardiovascular and kidney outcomes-Nursing Case Study).
Amidst 13,026 patients with an average follow-up of 3.0 years (interquartile range 2.3–3.8 years), the combined cardiovascular outcome occurred in 825 (12.7%) patients acquiring finer enone and 939 (14.4%) receiving placebo [hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.78–0.95; P = 0.0018]. The composite kidney outcome occurred in 360 (5.5%) patients obtaining finer enone and 465 (7.1%) securing placebo (HR, 0.77; 95% CI, 0.67–0.88; P = 0.0002). Overall safety outcomes were generally identical between treatment arms. Hyperkalemia resulting from permanent treatment discontinuation happened more frequently in patients acquiring finer enone (1.7%) than placebo (0.6%) (Cardiovascular and kidney outcomes-Nursing Case Study).
Conclusion
Finer enone minimized the risk of clinically significant cardiovascular and kidney outcomes vs. placebo beyond the spectrum of CKD in patients having type 2 diabetes (Cardiovascular and kidney outcomes-Nursing Case Study).
Key Question
Does finer enone, a novel selective, nonsteroidal mineralocorticoid receptor antagonist, added to maximum tolerated renin–angiotensin system inhibition lower cardiovascular disease and kidney disease progression over a broad range of chronic kidney disease in patients with type 2 diabetes?
Key Finding
In a prespecified, pooled lone-level analysis from two mixed trials, we established reductions both in cardiovascular events and kidney failure outcomes with finer enone. Moreover, owing o the fact that 40% of the patients experienced an estimated glomerular filtration rate of >60 mL/min/1.73m2 they remained identified solely based on albuminuria (Cardiovascular and kidney outcomes-Nursing Case Study).
Lesson to learn
Finer enone limits the risk of clinical cardiovascular outcomes and kidney disease progression more so, in a wide range of patients with chronic kidney disease and type 2 diabetes. Screening for albuminuria to identify at-risk patients among victims with type 2 diabetes facilitates lessening the burden of both cardiovascular and kidney disease (Cardiovascular and kidney outcomes-Nursing Case Study).
Structured Graphical Abstract
Keywords
Cardiorenal outcomes, Chronic kidney disease, Finer enone, Hospitalization for heart failure, Hyperkalemia, Type 2 diabetes
Topic:
hyperkalemia
kidney failure, chronic
heart failure
diabetes mellitus, type 2
kidney failure
cardiovascular system
safety
kidney
finerenone
Issue Section:
Diabetes and Metabolic Disorders
Introduction
Patients with chronic kidney disease (CKD) and type 2 diabetes possess extra cardiorenal morbidity and mortality, despite current therapies, and the risks of progression towards kidney failure and cardiovascular events increase with the severity and stage of CKD. Patients having advanced kidney disease, remain more likely to advance to dialysis. On the other hand, patients with highly preserved estimated glomerular filtration rate (eGFR) carry a greater lifetime risk of cardiovascular morbidity such as heart failure, myocardial infarction (MI), stroke, or dying from cardiovascular causes (Cardiovascular and kidney outcomes-Nursing Case Study).
Evidence shows that overactivation of the mineralocorticoid receptor (MR) results in inflammation and fibrosis in the heart, kidneys, and vasculature. Moreover, where the MR is highly expressed that can drive CKD and cardiovascular disease progression. Finer enone is a novel, selective, nonsteroidal MR antagonist (MRA) that blocks MR-mediated sodium reabsorption and MR overactivation. Consequently, Finer enone has demonstrated anti-inflammatory and anti-fibrotic effects in preclinical kidney and cardiovascular disease models (Cardiovascular and Kidney outcomes-Nursing Case Study).
The Finer enone vital in reducing kidney failure and disease progression in Diabetic Kidney Disease (FIDELIO-DKD) and Finer enone in reducing cardiovascular mortality and morbidity in Diabetic Kidney Disease (FIGARO-DKD) phase III trials remain complementary in nature, attributed to features such as their similar designs and endpoints. Jointly, they, form the largest cardiorenal outcomes programmed in CKD in type 2 diabetes till now. They inquired about the benefit and safety of finer enone, on top of maximum tolerated renin-angiotensin system inhibition, on kidney and cardiovascular outcomes in patients with mild-to-severe CKD in type 2 diabetes (Supplementary material online, Figure S1).
In FIDELIO-DKD, finer enone significantly diminishes the risk of the primary kidney composite outcome and the key secondary cardiovascular combined outcome in patients with predominantly stage 3–4 CKD with severely increased albuminuria and type 2 diabetes. In FIGARO-DKD, finer enone significantly cut off the primary cardiovascular composite outcome risk in a robust patient population than studied in FIDELIO-DKD (patients with stage 2–4 CKD and relatively increased albuminuria, or stage 1–2 CKD with severely increased albuminuria) (Cardiovascular and Kidney outcomes-Nursing Case Study).
The FIDELIO-DKD trial was depicted to detect a treatment effect of finer enone on kidney failure endpoints. On the other hand, the FIGARO-DKD trial purposed to detect an effect on a cardiovascular composite primary endpoint. To improve the ability to detect a treatment effect on the kidney failure outcome, patients having a higher urine albumin-to-creatinine ratio (UACR) were partially selected in the FIDELIO-DKD trial.
Moreover, to provide a greater kidney failure-free interval useful to detect a treatment effect on cardiovascular events, in FIGARO-DKD, a population with partial UACR and a wider eGFR range was selected. Hence, the two trials complement each other with a slight overlap in the populations studied, and their identical designs and overlapping research sites allowed for the comparison and pooling of their results (Cardiovascular and Kidney Outcomes-Nursing Case Study).
The success and safety of finer enone, however, have not been fully evaluated across the spectrum of CKD in type 2 diabetes. The Finer enone in chronic kidney disease and type 2 diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial program analysis (FIDELITY) pools these complementary studies with similar designs, assessments, and conduct. The FIDELITY prespecified pooled analysis aimed to provide more robust estimates of finer enone efficacy and safety across the spectrum of patients with CKD and type 2 diabetes, to provide reassurance regarding outcomes in a wide range of patients with a degree of precision that was not possible to obtain by considering the two trials separately (Cardiovascular and kidney outcomes-Nursing Case Study).
Methods
Study design
This prespecified pooled success and safety analysis, which remained prespecified in a formal statistical analysis plan, combines data from FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049), two phase III, randomized, double-blind, placebo-controlled, multicenter clinical trials (Table 1 and Supplementary material online, Figure S2). Trial design and study protocol details hence published previously.7 (Cardiovascular and Kidney outcomes-Nursing Case Study)
Table 1
Pooled analysis study details
| Study name | FIDELIO-DKD7 | FIGARO-DKD10 |
|---|---|---|
| Publication year | 2020 | 2021 |
| Study design | Phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial | Phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial |
| Sample sizea | 5734 | 7437 |
| Inclusion criteria | Age ≥18 yearsT2D and CKD defined as UACR 30–<300 mg/g, eGFR 25–<60 mL/min/1.73 m2, and diabetic retinopathy, or UACR 300–5000 mg/g and eGFR 25–<75 mL/min/1.73 m2Maximum tolerated dose of an RAS inhibitor Serum potassium ≤4.8 mmol/L | Age ≥18 yearsT2D and CKD defined as UACR 30–<300 mg/g and eGFR 25–90 mL/min/1.73 m2, or UACR 300–5000 mg/g and eGFR ≥60 mL/min/1.73 m2Maximum tolerated dose of an RAS inhibitor Serum potassium ≤4.8 mmol/L |
| Exclusion criteria | Non-diabetic kidney disease Uncontrolled hypertensionbHbA1c >12%SBP <90 mmHgChronic symptomatic HFrEFcRecent CV event Dialysis for acute kidney failure Kidney transplant | Non-diabetic kidney disease Uncontrolled hypertensionbHbA1c >12%SBP <90 mmHgChronic symptomatic HFrEFcRecent CV event Dialysis for acute kidney failure Kidney transplant |
| Follow-up period, median | 2.6 years | 3.4 years |
| Primary outcome | Time to kidney failure, sustained ≥40% decrease in eGFR from baseline, or renal death | Time to CV death, non-fatal MI, non-fatal stroke, or HHF |
| Secondary outcome | Time to CV death, non-fatal MI, non-fatal stroke, or HHF | Time to kidney failure, sustained ≥40% decrease in eGFR from baseline, or renal death |
| Trial registry information | NCT02540993 | NCT02545049 |
The key features of the FIDELIO-DKD and FIGARO-DKD studies that entailed the FIDELITY prespecified pooled analysis are described above, they include publication year, study design, sample size, eligibility criteria, average follow-up, primary and main secondary endpoints, and links to the trials’ ClinicalTrials.gov webpages (Cardiovascular and kidney outcomes-Nursing Case Study).
CKD, chronic kidney disease; CV, cardiovascular; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; HFrEF, heart failure having reduced ejection fraction; HHF, hospitalization for heart failure; MI, myocardial infarction; RAS, renin–angiotensin system; SBP, systolic blood pressure; T2D, type 2 diabetes; UACR, urine albumin-to-creatinine ratio (Cardiovascular and kidney outcomes-Nursing Case Study).
a
A combined total of 145 patients, (60 patients in FIDELIO-DKD and 85 patients in FIGARO-DKD) remained prospectively eliminated before database lock from all analyses as a result of a violation of critical Good Clinical Practice. As a result, this affected one site in the USA that was later closed during the conduct of the trial, hence, resulting in the elimination of 66 patients. In addition, during trial conduct, it was detected that several patients were combined simultaneously at multiple trial sites within the same locality in Florida, USA. This led to the prospective exclusion of a total of 79 patient IDs (Cardiovascular and kidney outcomes-Nursing Case Study).
b
Mean sitting SBP ≥170 mmHg or mean sitting DBP ≥110 mmHg at the run-in visit, or mean sitting SBP ≥160 mmHg or mean sitting DBP ≥100 mmHg at the screening visit (Cardiovascular and kidney outcomes-Nursing Case Study).
c
New York Heart Association class II–IV at the run-in visit.
Patients
Eligible patients were adults (aged ≥18 years) with type 2 diabetes and CKD treated with a maximum tolerated labeled dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) (Cardiovascular and Kidney Outcomes-Nursing Case Study).
Chronic kidney disease in FIDELIO-DKD
CKD in FIDELIO-DKD was defined as either: (i) persistent (demonstrated at both the run-in and screening visits, which took place between a minimum of 4 to a maximum of 16 weeks apart), moderately increased albuminuria (UACR ≥30–<300 mg/g) with an eGFR of ≥25–<60 mL/min/1.73 m2 and the presence of diabetic retinopathy, or (ii) persistent, severely increased albuminuria (UACR ≥300–≤5000 mg/g) and an eGFR of ≥25–<75 mL/min/1.73 m2 (Cardiovascular and Kidney outcomes-Nursing Case Study).
Chronic kidney disease in FIGARO-DKD
CKD in FIGARO-DKD was described as either: (i) persistent moderately increased albuminuria (UACR ≥30–<300 mg/g) with an eGFR of ≥25–≤90 mL/min/1.73 m2, or (ii) persistent, severely increased albuminuria (UACR ≥300–≤5000 mg/g) and an eGFR ≥60 mL/min/1.73 m2. Patients in both trials had to carry serum potassium ≤4.8 mmol/L at both the run-in and screening visits. Other key exclusion criteria entailed clinical diagnosis of symptomatic chronic heart failure having reduced ejection fraction (i.e., a Class IA recommendation for MRA treatment). Inclusion and exclusion criteria are listed in the Supplementary material online, Appendix (Cardiovascular and Kidney outcomes-Nursing Case Study).
Procedures
The procedures for the FIDELIO-DKD and FIGARO-DKD studies have been explained previously. Briefly, eligible patients were combined 1:1 to receive oral finer enone (10 or 20 mg) or a placebo. Both studies consisted of run-in, screening, double-blind treatment, and safety follow-up periods (Supplementary material online, Figure S2).7, 10 The run-in period required ACEi or ARB therapy to be balanced to a maximum tolerated labeled dose that did not result in unacceptable side effects. The study drug was withheld if potassium concentrations exceeded 5.5 mmol/L and restarted when potassium levels fell to ≤5.0 mmol/L. Further details are found in the Supplementary material online, Appendix (Cardiovascular and Kidney Outcomes-Nursing Case Study).
Outcomes
The outcome definitions for FIDELIO-DKD and FIGARO-DKD have been previously explained.7, 10 The significant outcomes selected for this analysis were either a primary or a secondary outcome or those predetermined in the hierarchical outcomes in the complementary studies. The efficacy results of interest for this pooled analysis were a combined cardiovascular outcome of time to cardiovascular death, non-fatal MI, non-fatal stroke, or hospitalization for heart failure (HHF), and a composite kidney outcome of time to first onset of kidney failure, sustained ≥57% decrease in eGFR from baseline over ≥4 weeks, or renal death (Cardiovascular and Kidney Outcomes-Nursing Case Study).
In the composite kidney outcome, kidney failure was described as end-stage kidney disease (ESKD) or a sustained decrease in eGFR to <15 mL/min/1.73 m2, and ESKD was defined as the initiation of chronic dialysis (for ≥90 days) or kidney transplantation. Other predefined outcomes included: a second composite kidney outcome of time to first occurrence of kidney failure, sustained ≥40% decrease in eGFR from baseline over ≥4 weeks, or renal death; time to all-cause mortality; time to all-cause hospitalization; and change in UACR from baseline to Month 4 (Cardiovascular and Kidney Outcomes-Nursing Case Study).
The eGFR ≥40% composite kidney outcome is the primary or secondary outcome in the complementary trials. However, a sustained ≥57% decrease in eGFR (equivalent to doubling of serum creatinine) was selected in FIDELITY since it is a classic outcome in diabetic nephropathy studies, and is a more robust kidney failure surrogate outcome than a ≥40% decrease in eGFR, particularly when initial changes in eGFR occur. This outcome was selected prior to data pooling and analysis. Furthermore, the eGFR ≥57% outcome was a predefined outcome in the complementary trials (Cardiovascular and Kidney outcomes-Nursing Case Study).
In the safety analyses, adverse events were considered treatment-emergent if they started or worsened during study drug intake or up to 3 days after any temporary or permanent interruption. The hyperkalemia management procedure has been previously explained (Cardiovascular and Kidney outcomes-Nursing Case Study).
References
Agarwal, R., Filippatos, G., Pitt, B., Anker, S. D., Rossing, P., Joseph, A., Kolkhof, P., Nowack, C., Gebel, M., Ruilope, L. M., & Bakris, G. L. (2022). Cardiovascular and kidney outcomes with finer enone in patients with type 2 diabetes and chronic kidney disease: The FIDELITY pooled analysis. European Heart Journal, 43(6), 474-484. https://doi.org/10.1093/eurheartj/ehab777
Perkovic, V., Jardine, M. J., Neal, B., Bompoint, S., Heerspink, H. J., Charytan, D. M., … & Mahaffey, K. W. (2019). Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. New England journal of medicine, 380(24), 2295-2306.
Bakris, G. L., Agarwal, R., Anker, S. D., Pitt, B., Ruilope, L. M., Rossing, P., … & Filippatos, G. (2020). Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. New England journal of medicine, 383(23), 2219-2229.
Agarwal, R., Kolkhof, P., Bakris, G., Bauersachs, J., Haller, H., Wada, T., & Zannad, F. (2021). Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine. European heart journal, 42(2), 152-161.
Ruilope, L. M., Agarwal, R., Anker, S. D., Bakris, G. L., Filippatos, G., Nowack, C., … & FIGARO-DKD study investigators. (2019). Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial. American journal of nephrology, 50(5), 345-356.
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