ARNI reduces adverse renal events and slows kidney function decline in HFpEF patients
This substudy of the PARAGON-HF trial demonstrated that in HFpEF patients, sacubitril/valsartan reduced the risk of a composite of renal outcomes and attenuated decline in kidney function compared to valsartan alone.
Angiotensin-Neprilysin Inhibition and Renal Outcomes in Heart Failure with Preserved Ejection FractionLiterature - Mc Causland FR, Lefkowitz MP, Clagget B et al. - Circulation. 2020 Aug 17. doi: 10.1161/CIRCULATIONAHA.120.047643.
Introduction and methods
Patients with heart failure (HF) have a higher prevalence of comorbidity of chronic kidney disease (CKD) and an increased risk of an adverse CV event compared to HF patients without CKD [1-3]. Inhibiting the renin-angiotensin system (RAS) in HF patients with reduced ejection fraction (HFrEF) reduces mortality and in diabetes slows down the course of proteinuric CKD [4-6]. However, blocking RAS in HF patients with preserved ejection fraction (HFpEF) has not led to a reduction in mortality or adverse renal events [7-10].
The angiotensin neprilysin inhibitor (ARNI) sacubitril/valsartan in HFrEF patients reduced CV mortality and HF hospitalization, and also slowed the rate of decrease in estimated glomerulus filtration rate (eGFR) [11,12]. In a subanalysis of the phase 2 PARAMOUNT trial the results suggest less decline in renal function with sacubitril/valsartan compared with valsartan only in a small group of HFpEF patients [13].
This study reports the pre-specified secondary renal outcome of the PARAGON-HF trial. The PARAGON-HF was a multicenter, double blind clinical trial of HFpEF patients with high prevalence of comorbidities [14], who were randomized to sacubitril/valsartan (n=2407) or valsartan alone (n=2389). The renal outcome in this substudy was a composite of ≥50% decline in eGFR relative to baseline, development of end-stage renal disease (ESRD), or renal death and an exploratory outcome was the overall effect of the treatment on eGFR decline in time. To assess the effect of drug administration on individual renal outcome, the cohort was divided into subgroups based on eGFR baseline kidney function (≥30 - <60 ml/min/1.73m2 and ≥60 ml/min/1.73m2). At baseline, the mean eGFR (±SD) was 63 (±19) ml/min/1.73m2. Total follow-up time was 129 weeks.
Main results
- There were less adverse renal events in the sacubitril/valsartan group (1.4%) compared to the valsartan only group (2.7%) (HR 0.50, 95% CI: 0.33-0.77, P<0.001).
- The sacubitril/valsartan group had a lower incidence of ≥50% decline in eGFR relative to baseline compared to valsartan, namely, 1.1% treated with sacubitril/valsartan compared to 2.5% with valsartan treatment (HR 0.44, 95% CI: 0.28-0.69). ESRD occurred in 0.3% of patients treated with sacubitril/valsartan compared to 0.5% of patients treated with valsartan (HR 0.58, 95% CI: 0.23-1.47). Renal death occurred in 2 patients; one in the sacubitril/valsartan group and one in the valsartan alone group.
- The decline in eGFR was attenuated for patients treated with sacubitril/valsartan (-2.0 ml/min/1.73 m2 per year [95%CI: 2.2 to -1.9]) compared with patients treated with valsartan (-2.7 ml/min/1.73 m2 per year [95%CI: -2.8 to -2.5]). The adjusted mean difference between sacubitril/valsartan and valsartan treatment was 0.6 ml/min/1.73 m2 per year (95% CI: 0.4-0.9, P<0.001). When additionally adjusted for blood pressure, the eGFR change difference was still 0.6 ml/min/1.73 m2 per year (95% CI: 0.3-0.8, P<0.001).
- No differences in treatment effects on renal outcome were observed between the two baseline eGFR groups (Pinteraction=0.92).
- Patients with baseline eGFR <60 ml/min/1.73 m2 treated with sacubitril/valsartan had, compared with the valsartan group, more episodes of hypotension, fewer episodes of elevated serum creatinine ≥2 mg/dL. Patients with baseline eGFR ≥60 ml/min/1.73 m2 in the sacubitril/valsartan group experienced fewer episode of elevated creatinine ≥2 mg/dL or hyperkalemic (≥6 mmol/L) events.
Conclusion
In this prespecified analysis of the PARAGON-HF trial, patients with HFpEF who were on sacubitril/valsartan had fewer renal outcomes and a slower decline of eGFR compared to those on valsartan. These effects were independent of baseline eGFR, indicating that sacubitril/valsartan may slow down renal function decline in patients with HFpEF.
References
1. Damman K, Valente MAE, Voors AA et al. Renal impairment, worsening renal function, and outcome in patients with heart failure: an updated meta-analysis. Eur Heart J. 2014;35:455–69.
2. Hillege HL, Nitsch D, Pfeffer MA et al. Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Investigators. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation. 2006;113:671–78.
3. Go AS, Yang J, Ackerson LM et al. Hemoglobin level, chronic kidney disease, and the risks of death and hospitalization in adults with chronic heart failure: the Anemia in Chronic Heart Failure: Outcomes and Resource Utilization (ANCHOR) Study. Circulation. 2006;113:2713–23.
4. Brenner BM, Cooper ME, de Zeeuw D et al. RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–69.
5. Lewis EJ, Hunsicker LG, Clarke WR et al. Collaborative Study Group. Renoprotective effect of the angiotensinreceptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851–60.
6. Parving HH, Lehnert H, Bröchner-Mortensen J et al. Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345:870–78.
7. Yusuf S, Pfeffer MA, Swedberg K et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet Lond Engl. 2003;362:777–81.
8. Cleland JGF, Tendera M, Adamus J et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J. 2006;27:2338–45.
9. Massie BM, Carson PE, McMurray JJ et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359:2456– 67.
10. Pitt B, Pfeffer MA, Assmann SF et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370:1383–92.
11. McMurray JJ, Packer M, Desai AS et al. Angiotensin neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371-993-1004
12. Damman K, Gori M, Claggett B et al. Renal Effects and Associated Outcomes During Angiotensin-Neprilysin Inhibition in Heart Failure. JACC Heart Fail. 2018;6:489–98.
13. 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 Lond Engl. 2012;380:1387–95.
14. Solomon SD, Rizkala AR, Lefkowitz MP et al. Baseline Characteristics of Patients With Heart Failure and Preserved Ejection Fraction in the PARAGON-HF Trial. Circ Heart Fail. 2018;11:e004962.