Trends in Kidney Function Outcomes Following RAAS Inhibition in Patients With Heart Failure With Reduced Ejection Fraction

Abstract

Rationale & objective: Angiotensin-converting enzyme (ACE) inhibitors are beneficial in heart failure with reduced ejection fraction (HFrEF). We sought to describe longitudinal trends in estimated glomerular filtration rate (eGFR) in HFrEF and how ACE-inhibitor therapy influences these changes.

Study design: Post hoc analysis of trial data.

Settings & participants: Symptomatic (Treatment Trial, n=2,423) and asymptomatic (Prevention Trial, n=4,094) patients from the Studies of Left Ventricular Dysfunction (SOLVD).

Exposure: Enalapril versus placebo.

Outcomes: Early and long-term eGFR slope (ie, within and after the first 6 weeks) and 4 kidney end points: (1) serum creatinine level increase by≥0.3mg/dL, (2)>30% eGFR decline, (3)>40% eGFR decline, and (4) incident eGFR<30mL/min/1.73m².

Analytical approach: Shared parameter models, multivariable Cox regression models.

Results: Baseline mean eGFR was lower in the Treatment Trial than in the Prevention Trial, 69.5±19.8 (SD) versus 76.2±18.6mL/min/1.73m². Following randomization, an early eGFR decline occurred in the enalapril group; however, slopes during the median 3-year follow-up were not statistically different by randomization arm in either the Treatment Trial (-0.84 in enalapril vs-1.36mL/min/1.73m² per year in placebo; P=0.08) or Prevention Trial (-1.27 in enalapril vs-1.36mL/min/1.73m² per year in placebo; P=0.7). Random assignment to enalapril treatment increased the risk for all 4 outcomes in the Treatment Trial in the first 6-week period (HRs were 1.48 [95% CI, 1.10-1.99] for creatinine increase by≥0.3mg/dL; 1.38 [95% CI, 0.98-1.94] for eGFR decline> 30%; 2.60 [95% CI, 1.30-5.21] for eGFR decline> 40%; and 4.71 [95% CI, 1.78-12.50] for eGFR<30mL/min/1.73m²), but after the first year was not significantly associated with increased risk. A similar albeit less pronounced pattern was observed in the Prevention Trial, with risks present only in the early period.

Limitations: Creatinine results were not blinded, making it possible that ACE-inhibitor/placebo dosing was influenced by creatinine level.

Conclusion: Kidney function decline is slow in HFrEF. Although random assignment to enalapril treatment results in a statistically increased risk for kidney surrogates, the risk is limited to the early phase and late eGFR slopes and risks are not different by randomly assigned group.

Keywords: ACE inhibitor; Angiotensin-converting enzyme (ACE); RAAS blockade; cardiorenal; chronic kidney disease (CKD) stage 4; eGFR slope; eGFR trajectory; enalapril; estimated glomerular filtration rate (eGFR); heart failure with reduced ejection fraction (HFrEF); kidney disease progression; kidney function; renal end point; renin-angiotensin-aldosterone system (RAAS).

Figure 1.

Mean estimated glomerular filtration rates (eGFR) over course of follow-up, stratified by trial and by randomization arm. Dotted lines represent 95% confidence intervals. Slopes were not significantly different between the Treatment and Prevention Trials (p=0.5).

Figure 2.

Kaplan-Meier plots of outcome-free survival, separated into the Treatment Trial and the Prevention Trial. Plots of incidence of creatinine increase by ≥0.3 mg/dl, decline in estimated glomerular filtration rate (eGFR) by >30%, decline in eGFR by >40% and incident eGFR to <30 ml/min/1.73 m². The number at risk can be found below each time separate plot.