PARAGON-HF: Kidney function and cardiovascular outcomes with sacubitril/valsartan

Chronic kidney disease (CKD) affects around half of people with heart failure with preserved ejection fraction (HFpEF) and is associated with a two-fold higher risk of death, compared with those without CKD. The presence of lower eGFR may, however, lead to hesitancy in initiating potentially beneficial therapies.

The angiotensin receptor–neprilysin inhibitor sacubitril/valsartan is used for the treatment of symptomatic heart failure with reduced ejection fraction. It has also been shown to slow the decline in eGFR in people with HFpEF, compared with the ARB valsartan. These benefits were independent of baseline eGFR and without higher risks of hyperkalaemia. Using data from the PARAGON-HF trial, the present study investigated whether the effects of sacubitril/valsartan on cardiovascular outcomes differ according to baseline kidney function in people with HFpEF.

The trial randomised 4795 participants, aged ≥50 years with chronic HF and left-ventricular ejection fraction (LVEF) ≥45%, to receive sacubitril/valsartan or valsartan. At baseline, mean eGFR was 67±19 mL/min/1.73 m², with 1955 (41%) having an eGFR of <45 mL/min/1.73 m². 

The primary cardiovascular outcome of cardiovascular death and total HF hospitalisations was met by 1902 participants. Compared with valsartan, sacubitril/valsartan reduced this outcome to a greater extent among those with lower baseline eGFR (P_interaction=0.07 for continuous eGFR). This treatment effect was most pronounced among those with eGFR ≤45 mL/min/1.73 m² (RR, 0.69 [95% CI, 0.51–0.94]). The treatment effect for cardiovascular death alone was non-linear and was noted to be greater in those with baseline eGFR <45 mL/min/1.73 m² (HR, 0.65 [95% CI, 0.43–0.97]). 

Further subgroup analyses revealed that the most pronounced treatment effects for the primary composite outcome were observed among those with eGFR ≤45 mL/min/1.73 m² and LVEF ≤57% (HR, 0.66 [95% CI, 0.45–0.97]) and for cardiovascular death alone.

PARAGON-HF found that the effect of neprilysin inhibition in reducing the frequency of HF hospitalisation and cardiovascular death was more pronounced at lower levels of baseline kidney function. Those with lower LVEF and coexisting CKD, who may typically have faced prescriber hesitancy, may particularly benefit from the initiation of this therapy.

The full article can be read here.