Finerenone vs. spironolactone to reduce adverse outcomes in patients with cardiac–kidney–metabolic syndrome complicated by atrial fibrillation: findings from the Tianjin atrial fibrillation project

What’s New?

1. This study first compares the prognostic improvement effects of finerenone and spironolactone in CKM syndrome patients combined with AF.

2. This article provides real-world data on the differences in the impact of finerenone and spironolactone on prognosis in the Chinese, filling the gap in data for Asian populations.

3. The improvement of adverse outcomes with finerenone may occur mainly in the early stage of treatment, within 6 months. However, due to the relatively small sample and short follow-up period, we should be cautious about this finding.

With the increase in the concept of cardio–kidney–metabolic (CKM) syndrome, atrial fibrillation (AF) is regarded as part of the cardiovascular system damage in CKM stage 4.¹ As a new type of non–steroidal mineralocorticoid receptor antagonists (MRAs), finerenone exhibits stronger anti-inflammatory and antifibrotic effects than spironolactone through sophisticated modulation of non-genomic effects related to aldosterone,² suggesting that finerenone may be a better choice compared to spironolactone for patients with AF.³ However, a few studies have compared and quantified the effect of finerenone and spironolactone on the prognosis in CKM syndrome patients complicated by AF. Thus, this study aims to evaluate the adverse outcomes in these patients treated with finerenone and spironolactone based on real-world data from Tianjin, China.

The data for this retrospective observational study were obtained from the Tianjin Atrial Fibrillation Project, approved by the Ethics Committee of the Second Hospital of Tianjin Medical University (IRB: KY2024045-01). The requirement for patient consent has been waived due to the use of deidentified data. Patients who met the following criteria were included in the study: (i) adult patients with a prescription of MRAs between January 2023 and September 2024 and (ii) patients diagnosed with AF before the first prescription of MRAs. The primary outcome was the composite of cardiovascular endpoints, kidney endpoints, and all-cause hospitalization. Cardiovascular endpoints included worsening heart failure (WHF) events (defined as hospitalization and urgent visits with both diagnosis of HF and additional administration of injectable diuretics, nitrites, and inotropic agents) and cardiovascular death.^4,5 Kidney endpoints included a sustained decline in eGFR ≥50% relative to baseline over at least 4 weeks, sustained eGFR decline <15 mL·min·1.73 m², initiation of dialysis, and renal transplantation.⁶ The secondary outcomes were each component of the primary outcome. Participants were followed until outcomes occurred or September 2024. The index date was defined as the time of the first prescription of MRA after AF diagnosis between 1 January 2023 to 30 September 2024. Baseline data and outcomes were extracted based on the index date. The analysis was performed based on the new user and intention-to-treatment design. To minimize baseline confounding factors, we used propensity score matching (PSM) to create two comparable groups (Finerenone group vs. Spironolactone group). Cox regression analyses were used to calculate the hazard ratio (HR) for the outcomes. Additionally, we did landmark analyses and calculated restricted mean survival time (RMST) to evaluate outcomes at 6 months and from 6 months to the end of the follow-up.

We enrolled a total of 8576 AF patients who had prescriptions for spironolactone and 144 AF patients who had prescriptions for finerenone. Among the overall patients, 66.9% had metabolic disorders, 47.1% had cardiac dysfunction, and 32.2% had renal dysfunction. After 1:3 matching, 126 patients in the finerenone group and 302 patients in the spironolactone group were finally included in the study, and the baseline characteristics were well-balanced between the two groups. During a median (interquartile range) follow-up of 180 days (IQR 86–313), the primary outcome was observed in 36 patients in the finerenone group and 134 patients in the spironolactone group. Cox regression analyses showed that finerenone was associated with 35% reduced risk of the primary outcome (HR: 0.64; 95%Cl: 0.45–0.93; P < 0.05). For cardiovascular events and all-cause hospitalization, no significant difference was observed in the two groups. Notably, landmark analyses showed that the rates of primary outcomes, cardiovascular events, and all-cause hospitalization were significantly reduced at 6 months, respectively, while no reduction was observed after 6 months (Figure 1A-1C). We further calculated the difference of RMST at 6 months between the two groups and found that for primary outcomes, cardiovascular events and all-cause hospitalization, the finerenone groups showed 20.05 (95%CI: 7.65–32.44), 10.34 (95%CI: 1.12–19.56), and 14.73 (95%CI: 3.15–26.32) more days of survival time, respectively (Figure 1D). Kidney endpoints occurred in four (3.2%) patients in the finerenone group, which was numerically less than the 16 (5.3%) in the spironolactone group. However, due to the small number of events, statistical analysis was not conducted.

Figure 1.

Cox regression analyses and landmark analyses focusing on the rates of primary outcomes (A), cardiovascular endpoints (B), and all-cause hospitalization (C) occurring before and after 6 months of the follow-up in CKM patients with complicated by AF treated with MRA (finerenone vs. spironolactone). RMST difference, RMST ratio, and RMTL ratio of primary outcomes, cardiovascular endpoints, and all-cause hospitalization in the finerenone group and the spironolactone group at 180 days (D). Abbreviations: Cardiac–kidney–metabolic syndrome: CKM; AF: Atrial fibrillation; MRA: Mineralocorticoid receptor antagonist; RMST: Restricted mean survival time; RMTL: Restricted mean time lost; HR: Hazards ratio; CI: Confidence interval.

This study is the first head-to-head study to compare the prognostic improvement effects of finerenone and spironolactone in CKM syndrome patients combined with AF. We found that finerenone showed greater reduction in the composite of cardiovascular endpoints, kidney endpoints, and all-cause hospitalizations. In this study, intention-to-treatment analysis of real-world data from new users validated the effectiveness of finerenone in the non–clinical trial environment and supplemented the external validity of existed randomized controlled trials^7,8 among AF patients prescribed finerenone. Moreover, previous real-world studies on finerenone were based on the TriNetX database.^6,9 The findings from the Tianjin Atrial Fibrillation Project provided data for the therapeutic effect of finerenone in the Chinese population.

Post hoc analysis demonstrated that baseline AF status did not affect the benefit of finerenone,³ but there are no real-world studies directly comparing the prognostic effects of finerenone and spironolactone in AF patients. Notably, for the primary outcome, cardiovascular endpoints, and all-cause hospitalization, the landmark analysis showed that finerenone significantly reduced the risk of adverse early outcomes (within 6 months) compared to spironolactone but did not for the late outcomes (after 6 months). One possible explanation for the difference in the early and late benefits was that the decline in medication adherence to MRA 6 months after initial prescription may have diluted the clinical benefit of the drug, thereby failing to observe statistically significant prognostic improvement. Given the observed significant clinical benefit of finerenone compared to spironolactone during the overall follow-up period, the results of this study supported finerenone as a potentially more promising option for improving prognosis in patients with AF when prescribing MRA. Furthermore, the results of the 6-month RMST showed an absolute difference of 20 days longer survival in the finerenone group. Although the absolute value of the survival extension was small, considering the restriction time was only 180 days, the relative effect of finerenone resulted in a 15% improvement in RMST and a 42.3% reduction in the survival time without adverse outcomes, further supporting the clinical advantage of finerenone. Future large-scale and long-term prospective studies may report more absolute benefit.

Mechanistically, aldosterone participates in chronic renin–angiotensin–aldosterone system activation, with impact on the incidence and progression of CKM syndrome.² For multiple comorbidities sharing similar mechanisms, such as inflammatory response, oxidative stress, insulin resistance, and vascular dysfunction, the stronger anti-inflammatory and anti-fibrotic effects of finerenone can produce a wide range of protective effects on multiple target organs.¹⁰

There are several limitations in this study. First, we lack the data of left ventricular ejection fraction and NTpro-BNP for all patients. However, we collected the NYHA class at baseline to assess cardiac function and adjusted the NYHA class as a covariate through PSM, maximally reducing confounding bias caused by baseline differences in cardiac function as much as possible. Second, due to the design of intention-to-treat analysis, we were unable to explore the impact of compliance on the therapeutic effect. Finally, since finerenone was recently introduced in China, the study had a small sample size and a short follow-up period. Hence, we should be cautious about the difference in the effect of finerenone on improving adverse outcomes at 6 months and after 6 months. With the increasing application of finerenone, large-scale prospective studies are expected to investigate its short-term and long-term cardio–renal benefits in Chinese populations combined with AF.

In conclusion, our study suggests that finerenone may have greater potential benefits compared to spironolactone in improving adverse outcomes for patients with CKM syndrome complicated by AF, providing real-world evidence from the Chinese population.

Funding

This work was supported by grants from the Tianjin Key Medical Discipline Construction Project (TJYXZDXK-3-006B, TJWJ2022XK013).

Data availability

The data in this study could be made available upon reasonable request to the corresponding authors.