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

• Published in: American journal of kidney diseases Vol. 75; no. 1; pp. 21 - 29
• Main Authors: McCallum, Wendy, Tighiouart, Hocine, Ku, Elaine, Salem, Deeb, Sarnak, Mark J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2020
• Subjects: ACE inhibitor; Aged; Angiotensin-converting enzyme (ACE); Angiotensin-Converting Enzyme Inhibitors - therapeutic use; Asymptomatic Diseases; cardiorenal; chronic kidney disease (CKD) stage 4; Creatinine - metabolism; eGFR slope; eGFR trajectory; enalapril; Enalapril - therapeutic use; estimated glomerular filtration rate (eGFR); Female; Glomerular Filtration Rate; Heart Failure - drug therapy; Heart Failure - metabolism; heart failure with reduced ejection fraction (HFrEF); Humans; kidney disease progression; kidney function; Male; Middle Aged; Mortality; Multivariate Analysis; Proportional Hazards Models; RAAS blockade; renal end point; Renal Insufficiency, Chronic - epidemiology; Renal Insufficiency, Chronic - metabolism; renin-angiotensin-aldosterone system (RAAS); Stroke Volume; kidney function; kidney disease progression; enalapril; renin-angiotensin-aldosterone system (RAAS); chronic kidney disease (CKD) stage 4; eGFR slope; RAAS blockade; cardiorenal; renal end point; heart failure with reduced ejection fraction (HFrEF); eGFR trajectory; estimated glomerular filtration rate (eGFR); Angiotensin-converting enzyme (ACE); ACE inhibitor
• ISSN: 0272-6386; 1523-6838
• DOI: 10.1053/j.ajkd.2019.05.010

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. Post hoc analysis of trial data. Symptomatic (Treatment Trial, n=2,423) and asymptomatic (Prevention Trial, n=4,094) patients from the Studies of Left Ventricular Dysfunction (SOLVD). Enalapril versus placebo. 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. Shared parameter models, multivariable Cox regression models. 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. Creatinine results were not blinded, making it possible that ACE-inhibitor/placebo dosing was influenced by creatinine level. 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.