Safia Chatur, MD: Sacubitril/Valsartan Offers Benefit in HFrEF Across New KDIGO Risk Classes

An analysis of data from PARADIGM-HF suggests sacubitril/valsartan (Entresto) provided consistent benefit across the spectrum of renal impairment among patients with heart failure with reduced ejection fraction (HFrEF).

Presented at the American College of Cardiology 2024 (ACC.24) Annual Scientific Sessions, the study assessed the effects of the angiotensin receptor–neprilysin inhibition across the recently published 2024 Kidney Disease Improving Global Outcomes (KDIGO) classifications, with results supporting use in patients with HFrEF across the spectrum of kidney risk included in PARADIGM-HF.¹

“Our key objective was to assess the relative treatment effects of sacubitril/valsartan across the critical risk categories in patients with reduced ejection fraction heart failure in the PARADIGM-HF trial. Despite facing elevated clinical risk, patients with concomitant chronic kidney disease and heart failure often also have higher rates of premature drug discontinuation,” explained lead investigator Safia Chatur, MD, clinical fellow at Massachusetts General Hospital and a research fellow at Brigham and Women’s Hospital, in an interview with HCPLive. “This is, in part, related to uncertainties around the safety and efficacy of established guideline directed medical therapy.”

Originally published in 2014, PARADIGM-HF was launched with the intent of evaluating sacubitril/valsartan against enalapril among 8422 patients with HFrEF and an eGFR of at least 30 ml/min/1.73m2. The trial randomized these patients in a 1:1 ratio to 200 mg twice daily or enalapril 10 mg twice daily. The trial was halted after a median of 27 months of follow-up due to efficacy, with results indicating the primary outcome of cardiovascular death for hospitalization for heart failure was reduced by 20% with sacubitril/valsartan relative to enalapril (Hazard Ratio [HR], 0.80; 95% Confidence Interval [CI], 0.73 to 0.87; P <.001).²

Since the trial was published, advances in understanding pathophysiology and breakthroughs in pharmacotherapy have revolutionized discussions around management of chronic kidney disease (CKD). This change is reflected in the recent updates in risk classification published by KDIGO. Published on March 13, 2024, the 2024 KDIGO risk classifications leverage both eGFR and UACR to better stratify risk in patients with CKD.³

Among those who underwent randomization in PARADIGM-HF, 1910 were included in the ACC.24 analysis based on available data related to UACR and eGFR. In this subgroup, 42%, 32%, and 26% were classified as low, moderate, and high or very high KDIGO risk, respectively. The primary outcomes of interest for Chatur and colleagues are a primary composite of cardiovascular death or heart failure hospitalization and a renal composite outcome of a sustained decline in eGFR by 40% or greater or end-stage kidney disease.¹

Upon analysis, results demonstrated a treatment effect of sacubitril/valsartan was observed across risk classifications, with no significant variation observed for those considered low (HR, 0.66; 95% CI, 0.47 to 0.93), moderate (HR, 0.82; 95% CI, 0.58 to 1.16), or high or very high risk (HR, 0.96; 95% CI, 0.70 to 1.32; P for interaction = .31). For the renal outcome, relative treatment effects were consistent across the low (HR, 0.76; 95% CI, 0.51 to 1.11) and moderate (HR, 0.53; 95% CI, 0.33 to 0.84) KDIGO risk categories, but this effect was not observed in those considered as high or very high risk (HR, 0.66; 95% CI, 0.40 to 1.07; P for interaction = .50).¹

For further insights into the study and its findings, check out our interview with Chatur from the conference floor at ACC.24.

Chatur has no relevant disclosures of note.

References

1. Chatur S, Neuen BL, Claggett BL, et al. Effects of Sacubitril/Valsartan Across the Spectrum of Renal Impairment in Patients With Heart Failure. J Am Coll Cardiol. Published online April 1, 2024. doi:10.1016/j.jacc.2024.03.392
2. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. doi:10.1056/NEJMoa1409077
3. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024;105(4S):S117-S314. doi:10.1016/j.kint.2023.10.018