Effects of HF therapies on standardized kidney outcomes in HF patients

Individual patient-level data analysis of 6 HF trials showed the treatment effects of steroidal MRAs, ARNI, and SGLT2 inhibition on standardized stringent kidney outcomes were either neutral or beneficial compared with comparators.

This summary is based on the publication of Butt JH, McMurray JJ, Claggett BL, et al. - Therapeutic Effects of Heart Failure Medical Therapies on Standardized Kidney Outcomes: Comprehensive Individual Participant-Level Analysis of 6 Randomized Clinical Trials. Circulation. 2024 Sep 1 [Online ahead of print]. doi: 10.1161/CIRCULATIONAHA.124.071110

Introduction and methods

Background

Kidney endpoints of drug trials for HF vary greatly due to a lack of a standard definition of such events [1]. This makes it difficult to interpret and compare the results of these trials.

Aim of the study

The authors assessed the effects of several HF therapies on different composite kidney outcomes across contemporary trials in patients with HFrEF and HFpEF.

Methods

For this analysis, individual patient-level data were collected from 6 RCTs of the steroidal MRAs eplerenone (EMPHASIS-HF) and spironolactone (TOPCAT Americas), the ARNI sacubitril/valsartan (PARADIGM-HF, PARAGON-HF), and the SGLT2 inhibitor dapagliflozin (DAPA-HF, DELIVER) [2-7]. In the EMPHASIS-HF, TOPCAT Americas, DAPA-HF, and DELIVER trials, placebo was the comparator, whereas sacubitril/valsartan was compared with enalapril (PARADIGM-HF) or valsartan (PARAGON-HF).

All patients with a serum creatinine measurement at randomization were included (n=28,690). eGFR values were calculated using the 2009 Chronic Kidney Disease Epidemiology Collaboration creatinine equation.

Outcomes

The standardized composite kidney endpoint was defined as: (1) a sustained eGFR decline (eGFR reduction confirmed by subsequent measurement ≥30 days later) ≥40%, ≥50%, or ≥57%; (2) end-stage kidney disease (ESKD; i.e., dialysis, kidney transplantation, or sustained eGFR decline to <15 mL/min/1.73 m²); or (3) renal death. The additional endpoint was ESKD only.

Main results

• When the most stringent definition of a sustained eGFR decline (≥57%) was applied, the proportion of patients experiencing the standardized composite kidney endpoint ranged from 0.3% to 3.3%.
• The proportion of patients experiencing the composite kidney endpoint with the least stringent definition of a sustained eGFR decline (≥40%) ranged from 1.0% and 10.0%.
• Treatment with a steroidal MRA doubled the risk of the composite kidney endpoint including a sustained eGFR decline ≥40% compared with placebo in the EMPHASIS-HF trial (HR: 1.98; 95%CI: 1.20–3.26) and TOPCAT Americas trial (HR: 1.95; 95%CI: 1.43–2.65).
• However, when more stringent definitions of a sustained eGFR decline (≥50% or ≥57%) were used, these treatment effects were less apparent and no longer significant.
• ARNI treatment appeared to consistently reduce the incidence of the composite kidney endpoint irrespective of the specific eGFR threshold used, although the reduction was only statistically significant with the ≥50% threshold in the PARAGON-HF trial (HR: 0.60; 95%CI: 0.40–0.92) and the ≥40% threshold in the same trial (HR: 0.60; 95%CI: 0.47–0.76).
• The potential beneficial effects of the SGLT2 inhibitor on the composite kidney endpoint were more apparent when defined by more stringent eGFR thresholds, although none of the effects were statistically significant.
• None of the HF therapies had a statistically significant effect on the occurrence of ESKD only compared with placebo.

Conclusion

In this individual patient-level data analysis of 6 contemporary HF trials, the event rate of the standardized composite kidney endpoint was largely influenced by applying different eGFR thresholds used to define a sustained eGFR decline, with higher event rates observed with less stringent definitions.

When a more stringent kidney outcome definition (including sustained eGFR decline ≥50% or ≥57%) was used, steroidal MRAs, ARNI, and SGLT2 inhibition had either neutral or beneficial effects on the composite kidney endpoint compared with the comparator arm. For steroidal MRA treatment, applying the least stringent definition (including sustained eGFR decline ≥40%) doubled the risk of the composite kidney endpoint compared with placebo. However, according to the authors, this “included acute declines in eGFR that might not ultimately reflect long-term effects on kidney disease progression.”

Find this article online at Circulation.

References

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