Bhandari S, Mehta S, Khwaja A, et al. Renin-Angiotensin System Inhibition in Advanced Chronic Kidney Disease. N Engl J Med. 2022 Nov 3. doi: 10.1056/NEJMoa2210639.

BACKGROUND: Renin-angiotensin system (RAS) inhibitors - including angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) - slow the progression of mild or moderate chronic kidney disease. However, the results of some studies have suggested that the discontinuation of RAS inhibitors in patients with advanced chronic kidney disease may increase the estimated glomerular filtration rate (eGFR) or slow its decline.

METHODS: In this multicenter, open-label trial, we randomly assigned patients with advanced and progressive chronic kidney disease (eGFR, <30 ml per minute per 1.73 m2 of body-surface area) either to discontinue or to continue therapy with RAS inhibitors. The primary outcome was the eGFR at 3 years; eGFR values that were obtained after the initiation of renal-replacement therapy were excluded. Secondary outcomes included the development of end-stage kidney disease (ESKD); a composite of a decrease of more than 50% in the eGFR or the initiation of renal-replacement therapy, including ESKD; hospitalization; blood pressure; exercise capacity; and quality of life. Prespecified subgroups were defined according to age, eGFR, type of diabetes, mean arterial pressure, and proteinuria.

RESULTS: At 3 years, among the 411 patients who were enrolled, the least-squares mean (±SE) eGFR was 12.6±0.7 ml per minute per 1.73 m2 in the discontinuation group and 13.3±0.6 ml per minute per 1.73 m2 in the continuation group (difference, -0.7; 95% confidence interval [CI], -2.5 to 1.0; P = 0.42), with a negative value favoring the outcome in the continuation group. No heterogeneity in outcome according to the prespecified subgroups was observed. ESKD or the initiation of renal-replacement therapy occurred in 128 patients (62%) in the discontinuation group and in 115 patients (56%) in the continuation group (hazard ratio, 1.28; 95% CI, 0.99 to 1.65). Adverse events were similar in the discontinuation group and continuation group with respect to cardiovascular events (108 vs. 88) and deaths (20 vs. 22).

CONCLUSIONS: Among patients with advanced and progressive chronic kidney disease, the discontinuation of RAS inhibitors was not associated with a significant between-group difference in the long-term rate of decrease in the eGFR. (Funded by the National Institute for Health Research and the Medical Research Council; STOP ACEi EudraCT number, 2013-003798-82; ISTRCTN number, 62869767.).

Ratings by Clinicians (at least 3 per Specialty)
Specialty Score
Internal Medicine
Family Medicine (FM)/General Practice (GP)
General Internal Medicine-Primary Care(US)
Comments from MORE raters

Family Medicine (FM)/General Practice (GP) rater

An incremental contribution to the literature. I would have preferred a blinded study, and I agree that the patient population is too narrow to permit generalization of the results.

Internal Medicine rater

This paper demonstrates that discontinuing RAAS inhibitors does not lead to any increases in kidney function as measured by EGFR over a 3-year period. Further, from a renal perspective, it's suggested that it doesn't make any difference whether these drugs are continued or not when the patient has advanced kidney dysfunction since blood pressure differences were ameliorated by choosing other anti-hypertensives. Based on these results, I won't be changing my clinical practice. If someone with advanced kidney disease, including patients on RRT, need anti-hypertensives and they are already on these medications, I'll continue. If not, I won't make a point of starting.

Internal Medicine rater

These are practice-changing results that are somewhat counterintuitive. It's disappointing given how little we have to modify severe CKD progression.

Nephrology rater

Glad to see this important study is completed. In a way, it is reassuring to the clinician knowing that continuing an RAS inhibitor does not accelerate progression because many patients require RAS inhibitors to keep BP in control. On the other hand, it is also reassuring that stopping RAS inhibitors does not quicken progression to ESKD. For patients prone to hyperkalemia, continuing RAS inhibitors is a big problem.

Nephrology rater

These results were unexpected. As a nephrologist, I expected that ACE inhibitors (ACEi) would result in improving cardiovascular morbidity and mortality in patients with stage 4 CKD. However, despite the many flaws in the methodology, I think nephrologists will now be more willing to continue patients on ACEi if there are standard renal or non-renal indications for this medication.

Nephrology rater

Long-awaited RCT of RASi discontinuation.