Kidney Function after RAAS Inhibition in Patients with HFrEF

In patients with heart failure with reduced ejection fraction (HFrEF), blockage of the renin-angiotensin-aldosterone system with either angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) is beneficial in reducing the risk for cardiovascular events. RAAS inhibition is considered an integral part of the management of patients with HFrEF. Therapy with ACE inhibitors or ARBs lead to dilation of the efferent arteriole in the kidney and can be associated with short-term declines in estimated glomerular filtration rate (eGFR). Previous studies in patients with diabetes have shown that early declines in eGFR following ACE inhibitor/ARB initiation are associated with slower long-term declines; it is unclear whether that trend applies to HFrEF.

A reduced level of kidney function in patients with HFrEF is a strong predictor of poor outcomes, and the mortality risk is increased in patients with eGFR <60 mL/min/1.73 m2. As eGFR declines, the mortality risk increases. However, there are few available data on longitudinal trends in patients with HFrEF. Declines in eGFR of 30% to 40% or greater as well as progression to chronic kidney disease (CKD) stage 4 are associated with increased risk for mortality and hospitalizations in the general population; the incidence of those kidney function end points are unclear in patients with HFrEF.

Wendy McCallum, MD, MS, and colleagues recently conducted a post hoc analysis of trial data to describe longitudinal trends in eGFR in HFrEF and how those changes are influenced by ACE-inhibitor therapy. Results of the analysis were reported in the American Journal of Kidney Diseases [2020;75(1):21-29].

The researchers utilized data from SOLVD (Studies of Left Ventricular Dysfunction), two multicenter, double-blind, randomized controlled trials sponsored by the National Heart, Lung, and Blood Institute. The two studies (Treatment Trial and Prevention Trial) were designed to assess the effects of the ACE inhibitor enalapril versus placebo on mortality in patients with HFrEF (ejection faction <35%).

The outcomes of interest of the current analysis were annual rate of decline in eGFR as well as four kidney function end points: (1) increase in serum creatinine level ≥0.3 mg/dL; (2) decline in eGFR >30% from baseline; (3) decline of eGFR >40%; and (4) incident eGFR <30 mL/min/1.73 m2.

A total of 2423 patients from the Treatment Trial and 4094 from the Prevention Trial were included in the analysis. Mean age was 60 years in the Treatment Trial and 59 years in the Prevention Trial; the Treatment Trial had a slightly higher percentage of women (19% vs 11% in the Prevention Trial). Baseline characteristics were generally similar across randomly assigned groups within each trial. There was a greater prevalence of diabetes, hypertension, and use of a diuretic in Treatment Trial participants; baseline eGFR was also worse in Treatment Trial participants (eGFR 69.5 mL/min/1.73 m2 vs 76.2 mL/min/1.73 m2 in the Prevention Trial).

Median follow-up was 34 months (range, 0.5 to 62.3 months). Among patients who were alive and reached each follow-up visit, there was no substantial difference in missing eGFR data by randomization arm in either trial.

There were early declines in eGFRs that were more pronounced in the enalapril arms of both trials, followed by parallel progressive declines in eGFRs over the remaining course of follow-up. There were no statistical differences in slopes during the median 3-year follow-up in either the Treatment Trial: –0.84 mL/min/1.73 m2 in the enalapril arm versus –1.36 mL/min/1.73 m2 in the placebo arm (P=.08) or the Prevention Trial: –1.27 mL/min/1.73 m2 in the enalapril arm versus –1.36 mL/min/1.73 m2 in the placebo arm (P=.7).

In the first 6-week period of the Treatment Trial, random assignment to the enalapril arm increased the risk for all four outcomes of interest: hazard ratio [HR], 1.48 (95% confidence interval [CI], 1.10-1.99) for creatinine increase by ≥0.3 mg/dL; HR, 1.38 (95% CI, 0.98-1.94) for eGFR decline >30%; HR, 2.60 (95% CI, 1.30-5.21) for eGFR decline >40%; and HR, 4.71 (95% CI, 1.78-12.50) for eGFR <30 mL/min/1.73 m2. After the first year, there was no significant association between treatment with enalapril and increased risk.

In the Prevention Trial, there was a similar, but less pronounced, pattern, with risks present only in the early period.

Limitations to the study cited by the authors included the exclusion of patients with serum creatinine levels >2.5 mg/dL from the original trial, and not collecting urinalyses as part of the trial.

In conclusion, the researchers said, “On average, decline in eGFR was relatively slow in both symptomatic and asymptomatic patients with HFrEF and only a small percentage reached incident CKD stages 4 to 5 during a median follow-up of 3 years. Random assignment to enalapril treatment only minimally hastened the progression of decline in kidney function. Despite a slightly increased risk for reaching several kidney function surrogate end points, the overall incidence of these end points was low and occurred early. Renin-angiotensin-aldosterone system inhibitors have been shown to have a clear mortality benefit for patients with HFrEF, as demonstrated in multiple landmark trials including SOLVS, and it is encouraging that their use appears to have minimal added risk for detriment to kidney function, although admittedly also no kidney benefit.”

Takeaway Points

  1. Patients with heart failure with reduced ejection fraction benefit from treatment with either angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), but it is not known whether early declines in estimated glomerular filtration rate (eGFR) following initiation of ACE-inhibitor/ARB therapy are associated with slower long-term declines.
  2. Researchers conducted a post hoc analysis of data from the Studies of Left Ventricular Dysfunction (SOLVD) trials (the Treatment Trial and the Prevention Trial).
  3. Random assignment to the enalapril arm in both trials resulted in statistically increased risk for four kidney surrogate end points; the risk was limited to the early trial phase and the overall incidence of the end points was low.