Acute declines in estimated glomerular filtration rate on enalapril and mortality and cardiovascular outcomes in patients with heart failure with reduced ejection fraction

Abstract

Angiotensin-converting enzyme inhibitors are beneficial in heart failure with reduced ejection fraction but are associated with acute declines in estimated glomerular filtration rate (eGFR). Prior studies evaluating thresholds of eGFR decline while using angiotensin-converting enzyme inhibitors in heart failure with reduced ejection have not taken into account this medication-driven decline. Here we used data from the Studies of Left Ventricular Dysfunction (SOLVD) trial of 6245 patients and performed Cox proportional hazards regression models to calculate hazard ratios of all-cause mortality and heart failure hospitalization-associated with percent eGFR decline at two- and six-weeks after randomization to enalapril versus placebo. In reference to placebo with equal degree of percent eGFR decline, any eGFR decline in the enalapril arm was associated with lower hazard of both outcomes. Under a conservative estimate using zero percent eGFR decline in the placebo arm as the reference, up to a 10% decline with enalapril was associated with mortality benefit (hazard ratio 0.87 [95% confidence interval 0.77, 0.99]) while up to a 35% decline was associated with decreased risk of heart failure hospitalization (0.78 [0.61, 0.98]). Under an intermediate estimate, up to a 15% decline with enalapril was associated with a mortality benefit (0.86 [0.77, 0.97]) and all levels of eGFR decline were associated with decreased risk of heart failure hospitalization. There was no percent eGFR decline, including up to 40%, in any models at either two- or six-weeks where enalapril was associated with higher mortality risk. Thus, in patients with reduced ejection fraction heart failure, enalapril is associated with decreased risk of mortality and heart failure hospitalizations. Hence, compelling reasons beyond moderate eGFR decline ought to be considered before its use is withdrawn.

Keywords: ACE inhibitor; SOLVD; cardiorenal syndrome; heart failure; kidney function decline.

Figure 1.. Representation of the potential different reference groups (a, b, c, d) for ascertainment of the hazard ratio for death for a 20% decline in eGFR (*).

Hazard ratio curves for varying changes in eGFR at 2-weeks after randomization to placebo and treatment were estimated by using restricted cubic spline modeling. The hazard ratio for death for a decline of 20% in eGFR at 2-weeks after randomization to enalapril (represented by the asterisk) could differ depending on the reference group,, with options a,b,c as potential reference groups drawn from randomized studies and option d as potentially drawn from observational studies. Option (a) as employed in much of the prior literature,^, would be a placebo patient with 20% eGFR decline, under the assumption that none of the decline on enalapril was due to hemodynamic decline; option (b) would be a placebo patient with 10% eGFR decline under the assumption that half of the decline on enalapril was due to hemodynamic effect; option (c) would be a placebo patient with 0% eGFR decline under the assumption that all of the decline on enalapril was due to hemodynamic effect. Option (d) would be an enalapril patient with 0% eGFR decline, as done in prior observational studies. HR indicates hazard ratio; eGFR indicates estimated glomerular filtration rate.

Figure 2.. Multivariable adjusted hazard ratios for all-cause mortality and heart failure hospitalization for those randomized to enalapril versus placebo according to magnitude of decline at 2-weeks (left), and 6-weeks (right).

Filled circles represent points at which there was a significant hazard ratio for enalapril group versus placebo. There was no significant interaction between decline and treatment at any time point. eGFR indicates estimated glomerular filtration rate, calculated using adjusted serum creatinine and CKD-EPI equation. P_interaction indicates p-value for interaction. Number of patients at each follow-up time point were 6245 at 2-weeks, and 6055 at 6-weeks. Models adjusted for age, sex, race, baseline kidney function, previous myocardial infarction, smoking, NYHA functional class, diastolic blood pressure, hematocrit, potassium, and trial.

Figure 3.. Multivariable hazard ratios for all-cause mortality and heart failure hospitalization for those randomized to enalapril or placebo according to magnitude of decline at 2-weeks (left), and 6-weeks (right).

Placebo, 0% eGFR held as reference point (represented by diamond). Filled circles represent points where hazard ratio for all-cause mortality is significant (p<0.05) compared to the reference point. eGFR indicates estimated glomerular filtration rate, calculated using adjusted serum creatinine and CKD-EPI equation. Number of patients at each follow-up time point were 6245 at 2-weeks, and 6055 at 6-weeks. Models adjusted for age, sex, race, baseline kidney function, previous myocardial infarction, smoking, NYHA functional class, diastolic blood pressure, hematocrit, potassium, and trial.