Renal effects of the angiotensin receptor neprilysin inhibitor LCZ696 in patients with heart failure and preserved ejection fraction

Voors AA, Gori M, Liu LC, et al.; for the PARAMOUNT Investigators
Eur J Heart Fail. 2015 Feb 6. doi: 10.1002/ejhf.232. [Epub ahead of print]

Background

Increases in serum creatinine are often seen when heart failure (HF) is treated with renin-angiotensin-aldosterone-system (RAAS) inhibitors [1]. Medication may be discontinued due to concern over worsening renal function.
The angiotensin receptor neprilysin inhibitor (ARNI) LCZ696 has been shown to be superior to enalapril in reducing the risk of death and of hospitalisation for HF in patients with HF with reduced ejection fraction (HFrEF) [2]. LCZ696 reduced NT-proBNP levels and was associated with left atrial reverse remodelling and improved symptoms in patients with HF with preserved EF (HFpEF) [3].
Although the renal effects of the components of LCZ696, namely the angiotensin II AT1 receptor antagonist valsartan and the neprilysin inhibitor AHU377, are known, the effect of LCZ696 on renal function in patient with HF have not been reported. In addition to inhibiting RAAS, which may lower eGFR, LCZ696 also increases natriuretic peptides that may be nephroprotective. Thus, its effect on renal function may differ from that of RAAS inhibition alone.
This study aimed to compare the effects of LCZ696 with valsartan on renal function in HFpEF. All 301 patients randomised in the PARAMOUNT [3] study were included for this analysis.

Main results

• Mean change in eGFR between baseline and 12 weeks of treatment did not differ between treatments. After 36 weeks, patients randomised to LCZ696 showed a smaller decline in eGFR than patients on valsartan (-1.5+ 13.1 vs. -5.2+11.4 mL/min.1.73m2, P=0.008).
• Mean change in cystatin C levels from baseline were similar between groups at 12 and 36 weeks.
• The geometric mean of urinary albumin to creatinine ratio (UACR) increased rapidly after initiation of treatment in the LCZ696 group (increase from 2.4 to 2.9 mg/mmol over 36 weeks), while it remained stable in the valsartan group (2.1 to 2.0 mg/mmol, P for difference at 36 weeks: 0.016). A sensitivity analysis of median UACR did not show a significant difference between treatments.
• 5% and 6% of patients in the LCZ696 group developed worsening renal function (WRF) at 12 and 36 weeks, as compared to 7% and 13% respectively in the valsartan group, but these differences were not statistically significant in adjusted analyses.
• 15 adverse events associated with the term ‘renal disorders (excluding nephropathies)’ were observed in the total group, of which 3 occurred in the LCZ696 group and 9 in the valsartan group (Fisher exact P=0.14).

Conclusion

This study shows that treatment with LCZ696 was associated with lower serum creatinine and higher eGFR after 36 weeks of treatment, as compared with valsartan. No differences in cystatin C levels were observed, and UACR was higher with LCZ696 than with valsartan.
In HF patients, changes in blood pressure often correspond to direct changes in GFR. Despite larger decrease in blood pressure in patients treated with LCZ696 [3], eGFR was better preserved as compared to patients on valsartan. These data suggest that the neprilysin inhibiting component in LCZ696 may neutralise the decline in GFR seen with valsartan, thereby preserving renal function in patients with HFpEF.

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References

1. Blankstein R, Bakris GL. Changes in kidney function following heart failure treatment: focus on renin-angiotensin system blockade. Heart Fail Clin 2008;4:425–438.
2. McMurray JJ, Packer M, Desai AS, et al, PARADIGM-HF Investigators and Committees. Angiotensin–neprilysin inhibition versus enalapril in heart failure.N Engl J Med 2014;371:993–1004.
3. Solomon SD, Zile M, Pieske B, et al, Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) Investigators. The angiotensin receptor neprilysin
inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet 2012;380:1387–1395.