IMPACT OF LOOP DIURETIC USE AT BASELINE ON KIDNEY OUTCOMES; A POST-HOC ANALYSIS IN THE STOP-ACEI TRIAL.

Introduction:

In the STOP-ACEi trial, outcomes were similar whether or not renin–angiotensin system inhibitors (RASi) were discontinued (Stop). We now investigate whether there was any interaction with the use of loop diuretics at time of randomization on renal outcomes.

Methods:

In this open label trial patients with eGFR<30 ml/min per 1.73m2 and progressive CKD were randomized to Stop or Continue RASi. The primary outcome was eGFR at 3-years. The composite of end-stage kidney disease (ESKD), >50% fall in eGFR, or kidney replacement therapy (KRT) was assessed as was time to KRT. Analyses were based on the intention-to-treat principle and were adjusted for the pre-specified minimization variables in the main trial (age, diabetes, mean arterial BP, proteinuria, eGFR) and baseline values. We used a repeated-measures, mixed-effects linear regression random slope model to estimate the between-group difference in eGFR at 3 years. Time and subgroup (if patient was on a diuretic at baseline or not) were included to allow for 3-way interactions among treatment, time, and subgroup. A Cox proportional-hazards model calculated Hazard ratios (HR) and 95% confidence intervals (CI). 

Results:

Of patients randomized to Continue or Stop RASi, 66 and 67 respectively were receiving a loop diuretic at baseline, while 139 in both groups were not. Median eGFR, arterial pressure and level of proteinuria were similar in all subgroups (Table 1). 

At 3y, among the 133 patients receiving loop diuretics at baseline, the least-squares mean (LSM) ± SE eGFR in ml/min/1.73m2 was 12.3±1.1 in the Stop group and tended to be lower at 10.1±1.2 in the continuation group (difference, 2.2; 95% CI, –0.9 to 5.4, negative values favouring continuation) (Fig 1 & Table 2). Among 278 patients not receiving loop diuretics at baseline, the LSM ± SE eGFR was 8.8 ± 0.8 in the Stop group and 11.6 ± 0.8 ml/min/1.73m2 in the Continue group (difference, –2.8; 95% CI, –4.9 to -0.8; Fig 1 & Table 2). Heterogeneity in outcome by subgroup was observed (P=0.04).

Secondary composite outcome of ESKD or initiation of KRT in the diuretic subgroup occurred in 37 (55%) and 36 patients (55%) respectively assigned to Stop and Continue groups (HR if stopped, 1.18; 95% CI, 0.74 to 1.89), while in the no diuretic subgroup it occurred in 91 (65%) and 79 patients (57%) respectively (HR if stopped, 1.33; 95% CI, 0.98 to 1.81) (Fig 2 & Table 2). No heterogeneity in outcome according to subgroup (P = 0.67, was observed after adjustment for minimization variable and treatment by diuretics Yes or No).

A composite of ESKD, initiation of KRT, or >50% decrease in eGFR in diuretic and no diuretic subgroups are detailed in Table 2. For the diuretic subgroup the relative risk if RASi was stopped was, 0.96 (95% CI, 0.76 to 1.20) while in the no diuretic subgroup it was 1.15 (95% CI, 0.99 to 1.33) (Table 2). There was evidence of heterogeneity in outcome according to subgroup (p=0.18).

Conclusions:

In this post-hoc subgroup analysis, use of loop diuretics at baseline was not associated with a clinically relevant difference in eGFR at 3 years. However, more patients who were not on a diuretic and discontinued RASi therapy progressed to the clinical endpoints of ESKD or KRT. RCTs are need in this subgroup. These data further support continuation of RASi in patients with advanced and progressive CKD whether treated with a loop diuretic or not.

I have no potential conflict of interest to disclose.

I did not use generative AI and AI-assisted technologies in the writing process.