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.
Drugs called angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, together known as renin–angiotensin system inhibitors, are used to treat high blood pressure, slow worsening kidney function and lower the risk of kidney failure (known as end-stage kidney disease which requires treatment with dialysis or kidney transplantation) in patients with early chronic kidney disease. However, we did not know if patients treated with renin–angiotensin system inhibitors and who have progressed to more advanced chronic kidney disease (stage 4 or 5) should stop or continue renin–angiotensin system inhibitors.
To determine whether stopping renin–angiotensin system inhibitors in people with advanced chronic kidney disease leads to an improvement or stabilisation of kidney function required a study comparing the outcomes of people who had had these drugs stopped with a group who continued these drugs (the STOP-angiotensin-converting enzyme inhibitors trial). We recruited 411 participants with advanced chronic kidney disease who were receiving renin–angiotensin system inhibitors from 37 kidney units in the UK, and randomly (like flipping a coin) allocated them to either stop or continue renin–angiotensin system inhibitors.
We then compared kidney function between the two groups at 3 years. We also assessed whether stopping or continuing renin–angiotensin system inhibitors had an influence on the development of end-stage kidney disease or need for kidney replacement therapy, the number of hospitalisations, blood pressure, quality of life and physical function. We collected data on safety outcomes including death and heart-related events (such as heart attacks).
The results of the trial showed no difference in kidney function at 3 years. The number of participants requiring dialysis, or a kidney transplant was also similar, as was the quality of life and physical function between the groups. Deaths and the number of heart events were similar in both groups.
This research suggests that there is no benefit in stopping renin–angiotensin system inhibitors in patients with advanced chronic kidney disease.
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