Study Finds RAS Inhibition Has Little Effect on Outcomes in Advanced Chronic Kidney Disease

For patients with advanced chronic kidney disease (CKD), discontinuing treatment with renin-angiotensin system (RAS) inhibitors was not associated with a significant change in estimated glomerular filtration rate (eGFR) or differences in long-term eGFR decline rates in a recent randomized study published in The New England Journal of Medicine.

RAS inhibitors, including angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), slow disease progression in patients with mild or moderate chronic kidney disease (CKD). Current guidelines are not clear-cut when it comes to continuing or discontinuing RAS inhibition for patients with advanced CKD.

A prior observational study suggested that RAS discontinuation in this patient population may increase eGFR. However, some studies suggest that RAS inhibition may increase eGFR or at least mitigate its decline in patients with advanced CKD. Inconsistent findings have made it difficult to determine the best course of action for patients on RAS inhibitors who progress to advanced CKD.

The multi-center, open-label, randomized STOP-ACEi study aimed to assess whether the discontinuation of RAS inhibition would increase or stabilize eGFR in patients with advanced and progressive CKD. Eligible patients were at least 18 years of age and had stage 4 or 5 CKD, with an eGFR of less than 30 mL per minute per 1.73m² of body surface area. Patients who were receiving dialysis or had undergone kidney transplantation were not eligible.

Patients included in the study also had to have experienced an eGFR decrease of 2 mL per minute per 1.73m² in the past 2 years. Having received treatment with an ACE inhibitor, ARB, or both for more than 6 months at the time of the study was also a requirement.

Patients were randomized to either continue receiving RAS inhibitors or discontinue RAS inhibitors. The main outcome was eGFR at 3 years, excluding eGFR values taken after renal replacement therapy. Secondary outcomes were incidence of end-stage kidney disease (ESKD), an eGFR decrease of more than 50%, initiation of renal replacement therapy, hospitalizations, blood pressure, and quality of life.

A total of 17,290 patients at 39 centers were screened, and 1210 patients were eligible for the trial. A total of 411 patients at 37 centers were randomized to either continue receiving RAS inhibitors (n = 205) or discontinue RAS inhibitors (n = 206). The median follow-up time was 3 years, and the median eGFR at baseline was 18 mL per minute per 1.73m².

At 3 years, the least-squares mean (±SE) eGFR was 12.6±0.7 mL per minute per 1.73 m² in the discontinuation cohort and 13.3±0.6 mL per minute per 1.73 m² in the continuation cohort. Outcomes favoring therapy continuation were seen throughout study subgroups stratified by age, eGFR, diabetes type, mean arterial pressure, and proteinuria.

After 3 years of follow-up, 128 of 206 patients (62%) in the discontinuation group had progressed to ESKD or received renal replacement therapy, compared with 115 of 205 (56%) in the continuation group. In the discontinuation group, 140 patients (68%) received renal replacement therapy or showed an eGFR decrease of more than 50%, versus 127 of 202 patients (63%) in the continuation group.

The incidence of hospitalization was similar between the groups, as were the incidences of adverse cardiovascular events and deaths. While the trial was not powered to investigate the effect of discontinuation or continuation on cardiovascular events or mortality, the findings do not provide much rationale to do so, the authors concluded.

“Although the use of RAS inhibitors has been found to slow the decline in eGFR in patients with mild or moderate chronic kidney disease, our findings are consistent with the possibility that these drugs may not be as helpful in patients with advanced and progressive chronic kidney disease,” the authors wrote.

Reference

Bhandari S, Mehta S, Khwaja A, et al. Renin-angiotensin system inhibition in advanced chronic kidney disease. N Engl J Med. 2022;387(22):2021-2032. doi:10.1056/NEJMoa2210639