Effects of enalapril in systolic heart failure patients with and without chronic kidney disease: Insights from the SOLVD Treatment trial

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Abstract

Background

Angiotensin-converting enzyme inhibitors improve outcomes in systolic heart failure (SHF). However, doubts linger about their effect in SHF patients with chronic kidney disease (CKD).

Methods

In the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial, 2569 ambulatory chronic HF patients with left ventricular ejection fraction 35% and serum creatinine level ≤ 2.5 mg/dl were randomized to receive either placebo (n = 1284) or enalapril (n = 1285). Of the 2502 patients with baseline serum creatinine data, 1036 had CKD (estimated glomerular filtration rate < 60 ml/min/1.73 m2).

Results

Overall, during 35 months of median follow-up, all-cause mortality occurred in 40% (502/1252) and 35% (440/1250) of placebo and enalapril patients, respectively (hazard ratio {HR}, 0.84; 95% confidence interval {CI}, 0.74–0.95; p = 0.007). All-cause mortality occurred in 45% and 42% of patients with CKD (HR, 0.88; 95% CI, 0.73–1.06; p = 0.164), and 36% and 31% of non-CKD patients (HR, 0.82; 95% CI, 0.69–0.98; p = 0.028) in the placebo and enalapril groups, respectively (p for interaction = 0.615). Enalapril reduced cardiovascular hospitalization in those with CKD (HR, 0.77; 95% CI, 0.66–0.90; p < 0.001) and without CKD (HR, 0.80; 95% CI, 0.70–0.91; p < 0.001). Among patients in the enalapril group, serum creatinine elevation was significantly higher in those without CKD (0.09 versus 0.04 mg/dl in CKD; p = 0.003) during first year of follow-up, but there was no differences in changes in systolic blood pressure (mean drop, 7 mm Hg, both) and serum potassium (mean increase, 0.2 mEq/L, both).

Conclusions

Enalapril reduces mortality and hospitalization in SHF patients without significant heterogeneity between those with and without CKD.

Introduction

Treatment with angiotensin-converting enzyme inhibitors (ACEIs) has been shown to reduce mortality and hospitalization in patients with systolic heart failure (SHF) or heart failure with reduced ejection fraction (HF-REF) [1], [2], [3]. However, these drugs are often underutilized, especially in those with chronic kidney disease (CKD) [4], [5], [6]. Although elevation of serum creatinine after initiation of ACEIs is temporary and not harmful to kidney function [7], this has been often cited as a reason for their non-use [7], [8], [9], [10]. As most randomized clinical trials (RCT) of ACEIs excluded patients with advanced CKD there is also lack of RCT evidence of their benefit in HF patients with CKD [11]. This is unfortunate as CKD is common among SHF patients and is associated with poor outcomes [12], [13], [14], [15]. Further, ACEIs have also been shown to reduce renal failure and prevent death in patients with CKD [16]. Therefore, the purpose of the current study was to evaluate the effect of enalapril on mortality and hospitalization in SHF patients with CKD in the Studies of Left Ventricular Dysfunction (SOLVD)-Treatment trial.

Section snippets

Source of data and study patients

SOLVD-Treatment was a randomized, double-blind, placebo controlled trial of enalapril, an ACEI, in patients with SHF, the rationale, design, and the results of which have been previously reported [2]. Briefly, 2569 ambulatory chronic HF patients with left ventricular ejection fraction ≤ 35% who were not currently receiving ACEIs were randomly assigned to receive either placebo (n = 1284) or enalapril (n = 1285) 2.5 to 20 mg/day. Patients were recruited from 89 hospitals in the United States, Canada,

Patient characteristics

Baseline characteristics of SHF patients with and without CKD in the placebo and enalapril groups are displayed in Table 1. Compared to patients without CKD, those with CKD were generally older, more likely to be women and have ischemic heart disease, and diabetes, and had a higher NYHA functional class, but were similar with respect to other characteristics.

Effect of enalapril on all-cause mortality in SHF patients with data on baseline kidney function

Among the 2502 SOLVD-Treatment participants with data on baseline serum creatinine, all-cause mortality occurred in 40% and 35% of

Discussion

Findings from the current study demonstrate that while enalapril significantly reduced the risk of all-cause and cardiovascular mortality in SHF patients without CKD, its effect on those with CKD was more modest and lacked significance. Furthermore, SHF patients with CKD seemed to derive benefit during the early years of follow-up and at below-target doses of enalapril. However, there was no significant heterogeneity in the effect of enalapril between SHF patients with and without CKD.

Funding and support

Dr. Bowling is supported by the Birmingham/Atlanta Department of Veterans Affairs Geriatric Research Education and Clinical Center, the John A. Hartford Foundation and the Southeast Center of Excellence in Geriatric Medicine. Dr. Sanders is supported by the NIH through grants (R01 DK046199 and P30 DK079337) and by the Department of Veterans Affairs through a Merit Award. Dr. Allman is supported by the NIH through grant 5UL1 RR025777. Dr. Ahmed is supported by the NIH through grants (R01-HL085561

Acknowledgments

The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.

References (25)

  • A. Ahmed et al.

    Renin–angiotensin inhibition in systolic heart failure and chronic kidney disease

    Am J Med

    (2012 Apr)
  • Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)

    N Engl J Med

    (1987)
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    “The Studies of Left Ventricular Dysfunction (SOLVD) trial was conducted and supported by the NHLBI in collaboration with the CHS Investigators. This manuscript was prepared using a limited access dataset obtained by the NHLBI and does not necessarily reflect the opinions or views of the SOLVD or the NHLBI.”

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