In a secondary analysis of PARADIGM-HF, the clinical benefits of sacubitril/valsartan versus enalapril on CV and renal outcomes were mostly consistent in patients with HFrEF across KDIGO risk categories.

This summary is based on the publication of 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. 2024 Apr 1:S0735-1097(24)06691-9. doi: 10.1016/j.jacc.2024.03.392.

Introduction and methods

Background

The 2024 KDIGO clinical practice guideline emphasizes the importance of robust estimation of kidney risk in patients with CKD, using both eGFR values and urine albumin creatine ratio (UACR) for kidney risk assessment [1]. Most trials of HF therapies have evaluated the efficacy of therapies relative to baseline eGFR. There is little data on the clinical benefits of HF medications using a 2 dimensional framework of kidney risk stratification.

Sacubitril/valsartan is a foundational therapy in the management of patients with HFrEF [2-3]. The treatment effect of sacubitril/valsartan versus enalapril is consistent in patients with and without CKD (as assessed according to eGFR and macroalbuminuria status individually) [4]. It is unclear whether the effects of sacubitril/valsartan are consistent across KDIGO risk categories in HF populations.

Aim of the study

The goal of this secondary analysis of PARADIGM-HF was to evaluate the prognostic significance of KDIGO risk categories in patients with HFrEF. Moreover, this analysis aimed to evaluate the relative treatment effects of sacubitril/valsartan across KDIGO risk categories in patients with HFrEF.

Methods

PARADIGM-HF was a double-blind, active-controlled, randomized trial in which the effects of sacubitril/valsartan versus enalapril were evaluated in 8399 adult patients with HFrEF and elevated natriuretic peptides. Prior to randomization, two consecutive run-in periods were followed: patients first received enalapril 10 mg twice daily and subsequently sacubitril/valsartan 100 mg twice daily, which was then uptitrated to sacubitril/valsartan 200 mg twice daily. Patients with eGFR <30ml/min/1.73m² were excluded.

This analysis included 1910 patients from PARADIGM-HF with available baseline eGFR and UCAR data, which was used to determine KDIGO risk. Patients from the high and very high risk categories of KDIGO were merged into one category. A total of 797 patients (42%) were classified as low KDIGO risk (defined as eGFR ≥60mL/min/1.73 m² and UACR <30 mg/g), 609 patients (32%) as moderate KDIGO risk (defined as eGFR ≥60 mL/ min/1.73 m² and UACR of 30-300 mg/g or eGFR 45 to <60 mL/min/1.73 m² and UACR <30 mg/g), and 605 patients (26%) as high or very high KDIGO risk (defined as eGFR< 45 mL/min/1.73 m² or UACR>300 mg/g or eGFR 45 to <60 mL/min/1.73 m² and UACR 30-300 mg/g).

Outcomes

The primary outcome was a composite of CV mortality or first HF hospitalization. A post hoc renal composite outcome was the composite of sustained decline in eGFR of ≥ 40% from baseline or end-stage kidney disease (i.e. dialysis, kidney transplantation, or a sustained decline in eGFR to <15mL/min/1.73m²).

Main results

CV outcomes

• Patients in the highest KDIGO risk categories had the highest rates of the composite of CV mortality or first HF hospitalization (low risk group: 7.6 [6.5-9.0] per 100py; moderate risk group: 0.4 [7.9-11.2] per 100py; high/very high risk group: 14.9 [12.7-17.6] per 100py; P<0.001). Similar results were observed for first HF hospitalization, CV mortality, and all-cause mortality.
• The treatment effect of sacubitril/valsartan on the primary outcome was mostly consistent across the spectrum of KDIGO risk categories compared with enalapril (HR: 0.66; 95%CI: 0.47-0.93 in the low risk group; HR: 0.82; 95%CI: 0.58-1.16 in the moderate risk group; HR: 0.96; 95%CI:0.70-1.32 in the high/very high risk group; P for interaction=0.31).

Renal outcome

• The post hoc renal composite outcome occurred in 252 patients. There were 105 events (13.2%) in the low risk group, 79 events (13.0%) in the moderate risk group, and 68 events (13.5%) in the high/very high risk group.
• In the overall cohort, sacubitril/valsartan versus enalapril reduced the risk of the renal composite outcome (HR: 0.65; 95%CI: 0.51-0.84). Treatment with sacubitril/valsartan versus enalapril reduced the risk of the renal composite outcome across KDIGO risk categories (HR: 0.76; 95%CI: 0.51-1.11 in the low risk group; HR 0.53; 95%CI: 0.33-0.84 in the moderate risk group; and HR: 0.66; 95%CI: 0.40-1.07 in the high/very high risk group; P for interaction=0.50).

Health-related quality of life

• In the overall cohort, treatment with sacubitril/valsartan versus enalapril improved KCCQ - Total Symptom Score (KCCQ-TSS) at month 8. The effect of sacubitril/valsartan versus enalapril on KCCQ-TSS was not consistent across KDIGO risk categories (difference of 1.0 points; 95%CI: -1.1-3.1 in the low risk group; -2.8 points; 95%CI: -5.2-0.4 in the moderate risk group; and 1.1 points; 95%CI: -2.0-4.2 in the high/very high risk group; P for interaction=0.05).

Safety

• The safety profile of sacubitril/valsartan versus enalapril was consistent across the KDIGO risk categories.

Conclusion

In this post hoc analysis of PARADIGM-HF, patients in the highest KDIGO risk groups experienced the highest rates of CV outcomes. The clinical benefits of sacubitril/valsartan versus enalapril on CV and renal outcomes were mostly consistent across the spectrum of KDIGO risk, with the exception of KCCQ-TSS.

Find this article online at J Am Coll Cardiol.

References

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2. McMurray JJV, Packer M, Desai AS, et al. Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. N Engl J Med. 2014 Sep 11;371(11):993-1004. doi: 10.1056/NEJMoa1409077
3. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022 May 3;79(17):1757-1780. doi: 10.1016/j.jacc.2021.12.011
4. Damman K, Gori M, Claggett B, et al. Renal Effects and Associated Outcomes During Angiotensin-Neprilysin Inhibition in Heart Failure. JACC Heart Fail. 2018 Jun;6(6):489-498. doi: 10.1016/j.jchf.2018.02.004