Sacubitril–valsartan combo good for kidneys in HFpEF

In patients with heart failure with preserved ejection fraction (HFpEF), angiotensin-neprilysin inhibition with sacubitril/valsartan confers better renoprotection than valsartan alone, reducing the risk of adverse renal events and the speed of decline in estimated glomerular filtration rate (eGFR), a study has found.

“Notably, these renal benefits appear to extend across the spectrum of baseline renal function, providing an important therapeutic option to slow renal function decline in patients with heart failure,” according to the investigators.

They evaluated the renal effects of angiotensin/neprilysin inhibition in 4,822 HFpEF patients enrolled in PARAGON-HF, among whom 2,419 received sacubitril/valsartan and 2,403 received valsartan alone.

At baseline, the mean eGFR was 63 ml/min/1.73 m², and the levels were below 60 ml/min/1.73 m² in 47 percent of the patients. This group tended to be older, female, have a history of diabetes, atrial fibrillation, or prior stroke, to be taking a diuretic, and less likely to be taking an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, and had lower systolic blood pressure than those with higher baseline eGFR (mean, 47 vs 77 ml/min/1.73 m²).

By the end of the study, the composite renal outcome (time to first occurrence of either ≥50 percent reduction in eGFR, end-stage renal disease, or death from renal causes) occurred in 33 patients (1.4 percent) on sacubitril/valsartan and 64 patients (2.7 percent) on valsartan monotherapy. [Circulation 2020;doi:10.1161/CIRCULATIONAHA.120.047643]

On multivariable Cox proportional hazard analysis, the combination halved the risk of the composite outcome (hazard ratio [HR], 0.50, 95 percent confidence interval [CI], 0.33–0.77; p=0.001). The 4-year risk was 2.1 percent on sacubitril/valsartan and 4.1 percent on valsartan alone, corresponding to a number needed to treat of 51.

The overall renoprotective benefit seen with the combination was driven by a lower incidence of ≥50-percent decrease in eGFR from baseline (1.1 percent vs 2.5 percent; HR, 0.44, 95 percent CI, 0.28–0.69). Additionally, it was consistent in subgroups defined by baseline eGFR (<60 and ≥60 ml/min/1.73 m²; p_interaction=0.92).

Finally, patients treated with sacubitril/valsartan showed less eGFR decline compared with those who received valsartan alone (–1.8 vs –2.4 ml/min/1.73 m² per year).

“Sacubitril/valsartan lowered systolic blood pressure (SBP) to a greater extent than valsartan in PARAGON-HF and was associated with a higher frequency of hypotensive events,” the investigators said. “Despite these differences, the occurrence of adverse renal events was lower with [the combination therapy].”

Indeed, in additional analyses controlling for changes in SBP, simultaneous inhibition of the renin-angiotensin and neprilysin systems was still more favourable in terms of a lower rate of decline in eGFR during the course of the study, they explained. Therefore, the beneficial renal effects are independent of blood pressure lowering.

The investigators acknowledged the presence of several study limitations. First, PARAGON-HF was not powered for analyses of the individual renal components, nor for assessment of differences in eGFR decline. Also, urine albumin/creatinine ratio was not measured in the study, which made it impossible to compare with PARADIGM-HF where, although CV benefits were maintained, modest increases in microalbuminuria were noted with sacubitril/valsartan vs enalapril.

“[Finally], PARAGON-HF excluded patients with more advanced kidney disease and had a modest proportion of non-Caucasians, thereby limiting generalizability of our findings to such populations,” they added.