ARNI may reduce adverse kidney outcomes in HF patients
Angiotensin-neprilysin inhibition and renal outcomes across the spectrum of ejection fraction in heart failure
Literature - Mc Causland FR, Lefkowitz MP, Claggett B et al., - Eur J Heart Fail 2022, doi: 10.1002/ejhf.2421Introduction and methods
Background
Use of angiotensin-converting enzyme inhibitors (ACEi) or mineralocorticoid receptor antagonists (MRAs) in patients with HFrEF has been associated with a decline in eGFR in post-hoc analyses [1,2]. In HFpEF patients, no renal benefits were observed with MRAs and an accelerated decline in renal function was observed with RAS inhibition [3-5]. In post-hoc analyses of HFrEF and HFpEF trials, decline in eGFR slowed with treatment of combined angiotensin-neprilysin inhibition [6,7].
This analysis examined the effect of sacubitril/valsartan on hard renal outcomes in heart failure and explored treatment effects according to ejection fraction by pre-specified pooling of data from the PARADIGM-HF and PARAGON-HF trials.
Methods
PARADIGM-HF and PARAGON-HF were randomized, double-blind trials in which sacubitril/valsartan was compared to a RAS inhibitor in patients with symptomatic heart failure and elevated natriuretic peptides. PARADIGM-HF enrolled 8399 patients with LVEF ≤40% and PARAGON-HF enrolled 4796 patients with LVEF ≥45%. One of the exclusion criteria was an eGFR<30 mL/min/1.73 m2 (at screening) or <25 mL/min/1.73 m2 (at randomization), or decrease >35% between screening and randomization.
Outcomes
The primary renal outcome was a composite of ≥50% reduction in eGFR, ESRD or death from renal causes.
Main results
- The composite renal endpoint occurred in 70 of 6594 patients (1.1%) in the sacubitril/valsartan group and in 123 of the 6601 patients (1.9%) in the RASi group (HR 0.56, 95%CI: 0.42-0.75, P<0.001).
- The treatment effect according to baseline EF was non-linear (P-interaction-0.35 for continuous EF and P-interaction=0.001 for categories of EF) and was most pronounced for those with baseline EF between 30% and 60%.
- There was no effect modification of treatment according to baseline eGFR.
- Mean decline in eGFR was -1.8 (95%CI: -1.9 to -1.7) mL/min/1.73 m² per year in the sacubitril/valsartan group and -2.4 (95%CI:-2.5 to -2.2) mL/min/1.73 m² per year in the RASi group (adjusted mean difference of 0.6, 95%CI: 0.4-0.7, P<0.001), and no evidence for effect modification according to baseline EF.
Conclusion
In this pooled analysis of PARADIGM-HF and PARAGON-HF consisting of patients with HFrEF and HFpEF, treatment with sacubitril/valsartan resulted in a reduction of the composite renal outcome and slowed the decline in eGFR compared with RAS inhibition.
The reduction in the renal composite outcome with use of sacubitril/valsartan compared with RAS inhibition was independent of baseline renal function and most pronounced in those with baseline EF between 30% and 60%.
References
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2.McCallum W, Tighiouart H, Ku E, Salem D, Sarnak MJ. Trends in kidney function outcomes following RAAS inhibition in patients with heart failure with reduced ejection fraction. Am J Kidney Dis 2019;75:21-9.
3.Beldhuis IE, Myhre PL, Claggett B, Damman K, Fang JC, Lewis EF et al. Efficacy and safety of spironolactone in patients with HFpEF and chronic kidney disease. JACC Heart Fail 2019;7:5-32.
4. Damman K, Solomon SD, Pfeffer MA, Swedberg K, Yufuf S, Young JG, et al. Worsening renal function and outcome in heart failure patients with reduced and preserved ejection fraction and the impact of angiotensin receptor blocker treatment: data from the CHARM-study programme. Eur J Heart Fail. 2016;18:1508-17.
5. Damman K, Perez AC, Anand IS, Komajda M, McKelvie RS, ZIle MR et al. Worsening renal function and outcome in heart failure patients with preserved ejection fraction and the impact of angiotensin receptor blocker treatment. J Am Coll Cardiol 2014; 64:1106-13.
6. Damman K, Gori M, Claggett B, Jhund PS, Senni M, Lefkowitz MP et al. Renal effects and associated outcomes during angiotensin-neprilysin inhibition in heart failure. JACC Heart Fail 2018;6:489-98.
7. Mc Causland FR, Lefkowitz MP, Claggett B, Anavekar NS, Senni M, Gori M et al. Angiotensin-neprilysin inhibition and renal outcomes in heart failure with preserved ejection fraction. Circulation 2020;142:1236-45.
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