Long‐Term Renal Function and Clinical Outcomes of Sacubitril/Valsartan in HFrEF and Stage 3–4 Chronic Kidney Disease: A 24‐Month Single‐Centre Cohort

Figures

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  Figure 1. Study flow diagram and analytical cohort. Of 370 consecutive patients with HFrEF and Stage 3–4 CKD initiating sacubitril/valsartan (S/V), 10 were excluded (5 inaccessible overseas follow‐up, 4 non‐adherent without follow‐up data, 1 heart transplantation at month 3), leaving 360 analyzed. At 24 months, 338 survived and contributed to paired longitudinal analyzes (eGFR, NT‐proBNP, CRP and NYHA n = 338; 6‐min walk distance n = 310); 22 died (all‐cause mortality 6.1%). Twelve patients (3.3%) met the primary renal composite (sustained ≥ 30% eGFR decline [n = 8] or ESKD/chronic dialysis [n = 4]). No patient with a renal composite event died within 24 months, so the renal (n = 12) and mortality (n = 22) branches are mutually exclusive. eGFR, estimated glomerular filtration rate; ESKD, end‐stage kidney disease.

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  Figure 2. Paired changes in renal function, neurohormonal activation and inflammation from baseline to 24 months among survivors (n = 338). Box‐and‐whisker plots show median, interquartile range and whiskers to data extremes. (A) eGFR (mL/min/1.73 m2; linear scale): primary emphasis is the total‐cohort (N = 360) linear mixed‐model slope (+0.04/month, 95% CI −0.02 to +0.10; annualized +0.48/year, 95% CI −0.24 to +1.20; LMM p = 0.185; paired within‐survivor change +1.5, paired p = 0.004). (B) NT‐proBNP (ng/L; log scale; geometric mean ratio 0.29, 95% CI 0.25–0.34; LMM p < 0.001). (C) CRP (mg/L; log scale; Hodges–Lehmann shift −0.5, 95% CI −0.8 to −0.3; paired p < 0.001).

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  Figure 3. NYHA functional class transitions from baseline to 24 months among survivors (n = 338). Stream widths are proportional to patient numbers. No patient was in NYHA class I at baseline; at 24 months 86.4% (292/338) were in class I (40.8%) or II (45.6%) and no survivor remained in class IV (vs 11.2% at baseline). Stuart–Maxwell marginal‐homogeneity test χ 2 = 252.85, df = 3, p < 0.001. NYHA, New York Heart Association.

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  Figure 4. Cumulative incidence of the primary renal composite endpoint by CKD stage. Aalen–Johansen cumulative incidence function (CIF) estimates with 95% confidence intervals (shaded bands), treating all‐cause death (n = 22) as a competing event. The event‐free number at risk is shown below the plot. At 24 months the renal composite incidence was 1.7% (95% CI: 0.3–4.1; 3/176) in Stage 3 and 4.9% (95% CI: 2.2–8.4; 9/184) in Stage 4 (Gray's test χ 2 = 2.91, p = 0.088). CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate.

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  Figure 5. All‐cause and cardiovascular mortality by CKD stage. (A) Kaplan–Meier all‐cause mortality (22 deaths; Stage 3 7/176 [4.0%] vs Stage 4 15/184 [8.2%]; log‐rank p = 0.101; 24‐month survival 96.0% vs 91.8%). (B) Aalen–Johansen cumulative incidence of cardiovascular death (14 deaths; Stage 3 4/176 [2.3%] vs Stage 4 10/184 [5.4%]) treating non‐cardiovascular death (n = 8) as a competing event (Gray's test p = 0.123). Number‐at‐risk arrays are shown below each panel. CKD, chronic kidney disease.