Withdrawal of renin-angiotensin system inhibitors’ effect on estimated glomerular filtration rate in adults with advanced kidney disease: the STOP-ACEi RCT
Authors: Bhandari Sunil , Mehta Samir , Khwaja Arif , Cleland John , Ives Natalie , Brettell Elizabeth , Chadburn Marie , Cockwell Paul , for the STOP-ACEi Trial Investigators  
Published: May 2023

Background
Renin–angiotensin system inhibitors, both angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, slow progression of mild and moderate chronic kidney disease. However, some evidence suggests that discontinuation of renin–angiotensin system inhibitors in patients with advanced chronic kidney disease might increase estimated glomerular filtration rate or slow its decline.

Objective
To test the hypothesis that stopping angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, or a combination of both, compared with continuing these treatments, improves or stabilises kidney function in patients with progressive stages 4 or 5 chronic kidney disease based on assessment of kidney function using the modification of diet in renal disease four-variable estimated glomerular filtration rate at 3 years, follow-up.

Setting
Thirty-seven UK hospitals with kidney services.

Design
An investigator-led multicentre open-label, randomised controlled trial of 411 participants with advanced (stage 4 or 5) progressive chronic kidney disease.

Participants
Adult patients with advanced (estimated glomerular filtration rate < 30 ml/minute/1.73 m2) and progressive chronic kidney disease who were receiving either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, or a combination of both.

Interventions
Participants were randomised in a 1 : 1 ratio using a centralised internet-based system to either discontinue renin–angiotensin system inhibitors (n = 206) or continue renin–angiotensin system inhibitors (n = 205).

Main outcome measures
The primary outcome was the estimated glomerular filtration rate at 3 years; measurements of estimated glomerular filtration rate made after commencing kidney replacement therapy were excluded. Secondary outcomes included development of end-stage kidney disease or starting kidney replacement therapy, a composite of either a > 50% decline in estimated glomerular filtration rate or commencement of kidney replacement therapy (including end-stage kidney disease), cystatin C, hospitalisations, blood pressure, exercise capacity and quality of life. Cardiovascular events, death and safety were recorded.

Results
At 3 years, the least-squares mean (± standard error) estimated glomerular filtration rate was 12.6 ± 0.7 ml/minute/1.73 m2 in the discontinuation group and 13.3 ± 0.6 ml/minute/1.73 m2 in the continuation group [difference −0.7, 95% confidence interval (−2.5 to 1.0; p = 0.42)] with a negative value favouring the continuation group. The treatment effect did not differ (heterogeneity) when data were analysed by the pre-specified subgroups. End-stage kidney disease or kidney replacement therapy occurred in 128 (62%) and 115 (56%) participants randomised to the discontinue and continue renin–angiotensin system inhibitor groups, respectively (hazard ratio 1.28, 95% confidence interval 0.99 to 1.65). The numbers of cardiovascular events and deaths observed were similar for those randomised to discontinue (108 events and 20 deaths) or continue (88 events and 22 deaths) renin–angiotensin system inhibitors.

Limitations
Non-white ethnic backgrounds were poorly represented, limiting the generalisability of our findings. The open-label nature of the trial may have affected clinical care and subjective end points, such as quality of life and exercise capacity. We only included patients who were receiving renin–angiotensin system inhibitors at the time of randomisation, thus excluding those who had already discontinued these agents.

Conclusions
Discontinuing renin–angiotensin system inhibitors in advanced and progressive chronic kidney disease does not cause a clinically relevant change in estimated glomerular filtration rate or difference in its long-term decline.

Future work
Future work should focus on updating clinical guidelines. Further analyses, in addition to the prespecified analyses, may be undertaken if new estimated glomerular filtration rate equations are introduced into clinical practice. Subgroup analysis by kidney disease aetiology and gender may be undertaken to look for potential differences in outcome in specific groups.

Trial registration
This trial is registered as STOP ACEi EudraCT Number, 2013-003798-82; ISRCTN62869767.

Funding
This award was funded by the Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 11/30/07), a Medical Research Council (MRC) and National Institute for Health and Care Research (NIHR) partnership. This is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 5. See the NIHR Funding and Awards website for further award information.