Plain English Summary
Background and study aims
Chronic kidney disease (CKD) affects 1 in 10 adults in the UK and describes progressive loss of kidney function regardless of the original kidney disease. CKD can have serious effects for those affected, including a risk of CKD progressing to complete kidney failure so that replacement of kidney function by dialysis or transplantation is required. Kidney disease is expensive with a high proportion of the health-care budget spent on CKD; the cost of dialysis alone is about £30,000 per year. Patient quality of life can be poor, with dialysis leading to early death. Treating high blood pressure (BP) is the most important intervention that can slow CKD progression. Some people with CKD gain additional protection from a type of drug, Angiotensin Converting Enzyme inhibitors (ACEi) or Angiotensin Receptor Blockers (ARBs). These drugs treat high BP but also slow CKD progression by other means. However, recent research suggests that in some people with advanced CKD (stages 4 & 5) who are progressing to complete kidney failure and are receiving treatment with an ACEi and/or ARB, stopping these drugs leads to stabilisation and improvement of kidney function and decreases or delays the need for dialysis. This indicates that in some patients the very tablets used to protect the kidneys may be contributing to a harmful decline in their function by some currently unknown mechanism. To date, research on this is observational and a study to confirm the association between stopping these drugs and stabilisation of kidney function is required. In this study we will randomly allocate suitable participants to either continue or stop their ACEi/ARB treatment and follow-up participants for 3 years. This study is needed before this treatment strategy can be put into routine clinical practice. In addition, the study will look at the other effects of stopping these drugs such as cardiovascular effects and participant quality of life.
Who can participate?
Men and women, aged 18 years and older, diagnosed with chronic kidney disease.
What does the study involve?
Participants are randomly allocated to either continue or discontinue their ACEi and/or ARB treatment.
What are the possible benefits and risks of participating?
Participants in studies such as this receive very close monitoring, which will be advantageous to their general health. Although participants may not receive any individual benefit from taking part in the study, the information we get from the study may help us to improve the treatment of all people in the UK with stage 4 or 5 CKD in the future. It is not currently known whether treating people with advanced CKD with ACEi and/or ARBs is beneficial or not. For participants that are allocated to continue with their current ACEi and/or ARB treatment, there will be no additional risk in the study than would normally be encountered in routine clinical care, but if the assumption of this study is correct, there is the risk that the participants CKD may get worse by staying on ACEi and/or ARBs. For participants that are allocated to the discontinuation group, there is the risk that stopping their existing ACEi and/or ARB treatment will cause a loss of the protective effect of ACEi and/or ARBs and an increase in blood pressure. To counteract the loss of antihypertensive therapy (drugs to lower blood pressure), participants that stop their ACEi and/or ARBs will start alternative antihypertensive drugs (e.g. calcium channel blockers, diuretics etc). However, drug withdrawal requires close monitoring and the potential risk of increased cardiovascular events for participants will be carefully assessed throughout the study by the Date Monitoring and Ethics Committee. If the results of the study show a benefit for ACEi/ARB withdrawal, it could have a huge impact on patients, their families and health services, by reducing or delaying the need for dialysis and kidney transplantation. Risk is minimised by ensuring that patients are closely monitored and that blood pressure is controlled by alternative means throughout the study. If the treating clinician feels that ACEi/ARB is required, this will be permitted. In patients with advanced CKD there are theoretical reasons why ACEi/ARB may be useful, useless or harmful. In practice, some clinicians withdraw these agents in patients with advanced CKD but others do not. It is important for care of patients that controversy and debate evolves into evidence-based guidelines.
Where is the study run from?
The study will be run at about 20 sites in Britain. For an up-to-date list of hospitals taking part in the study, please see the study website http://www.birmingham.ac.uk/STOPACEi
When is the study starting and how long is it expected to run for?
April 2014 to January 2020
Who is funding the study?
National Institute for Health Research (NIHR) (UK)
Who is the main contact?
15908; EME 11/30/07
Multi-centre randomised controlled trial of angiotensin converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB) withdrawal in advanced renal disease: the STOP-ACEi trial
That stopping ACEi or ARB treatment, or a combination of both, compared with continuing on these treatments, improves or stabilises renal function in patients with progressive stage 4 or 5 CKD based on assessment of renal function using the Modification of Diet in Renal Disease (MDRD) 4-variable estimated Glomerular Filtration Rate (eGFR) at 3 years follow-up.
Yorkshire and The Humber (Leeds East) Research Ethics Committee, 29/01/2014, ref: 13/YH/0394
Randomised; Interventional; Design type:Treatment
Primary study design
Secondary study design
Randomised controlled trial
Patient information sheet
Topic: Renal and Urogenital; Subtopic: Renal and Urogenital (all Subtopics); Disease: Renal
Participants will be randomly allocated to either continue or discontinue their ACEi and/or ARB treatment.
Continue ACEi/ARB arm: participants will continue with their current, standard treatment with ACEi and/or ARBs. The choice and dose of ACEi/ARB will be at the treating clinicians discretion.
Discontinue ACEi/ARB arm: participants will stop their existing ACEi and/or ARB treatment and will be started on alternative standard antihypertensives to ensure continued blood pressure control. The choice and dose of antihypertensives will be at the treating clinicians discretion.
Follow Up Length: 36 month(s)
Study Entry : Single Randomisation only
Lisinopril, Enalapril Maleate, Ramipril, Captopril, Cilazopril, Fosinopril Sodium, Moexipril Hydrochloride, Perindopril, Erbumine, Perindopril Arginine, Quinapril, Trandolapril, Imidapril Hydrochloride, Candesartan, Irbesartan, Telmisartan, Eprosartan, Losartan, Olmesartan, Valsartan, Azilsartan
Primary outcome measures
Renal function measured using MDRD 4-variable eGFR at 3 years
Secondary outcome measures
2. Blood pressure
3. Number of participants starting renal replacement therapy or sustaining a >50% decline in eGFR
4. Time taken to reach ESRD or need for renal replacement therapy
5. Hospitalisation rates from any cause
6. Participant quality of life and wellbeing (measured using the KDQOL-SF™ v1.3 questionnaire)
7. Participant physical function (measured using the 6-minute walk test)
8. That withdrawal of these treatments does not cause excess harm (e.g. increased cardiovascular events such as heart failure, hypertension, myocardial infarction, stroke) and is not associated with an increase in adverse effects
10. Urine protein excretion
11. Haemoglobin concentration
12. Dose of ESA
Overall trial start date
Overall trial end date
Participant inclusion criteria
1. Aged ≥18 years (male or female)
2. CKD stage 4 or 5 (eGFR <30 ml/minute using the MDRD equation) and not on dialysis therapy
3. Progressive deterioration in renal function (fall in eGFR of >2 ml/min/year over previous 12-24 months) as measured by linear regression analysis. A simple excel spreadsheet for calculation of this will be provided to all sites. A minimum of 3 measurements of eGFR over the previous 12-24 months are required to identify a >2 ml/min/year fall. The last eGFR must be within 3 months of randomisation
4. Treatment with either an ACEi or ARB, or a combination of both, for >6 months with at least 25% of the maximum recommended daily dose on the day of consent
5. Resting blood pressure (BP) ≤160/90 mmHg when measured in accordance with British Hypertension Society guidelines in clinic or home blood pressure readings within the previous month or a 24 h ambulatory blood pressure measurement within the last 3 months are acceptable
6. At least 3 months of specialist renal follow-up at the time of entry into the trial
7. Written, signed informed consent to the trial
Target number of participants
Planned Sample Size: 410; UK Sample Size: 410
Participant exclusion criteria
1. Aged <18 years
2. Uncontrolled hypertension (>160/90 mmHg) or requirement for 5 or more agents to control BP
3. Undergoing dialysis therapy
4. Any condition which, in the opinion of the investigator, makes the participant unsuitable for trial entry due to prognosis/terminal illness with a projected survival of less than 12 months
5. History of myocardial infarction or stroke in preceding 3 months
6. Participation in an interventional research study in preceding 6 weeks
7. Pregnancy, confirmed by positive pregnancy test, or breastfeeding
8. Inability to provide informed consent (e.g. due to cognitive impairment)
9. Immune-mediated renal disease requiring disease-specific treatment
10. Known drug or alcohol abuse
11. Inability to comply with the trial schedule and follow-up
Recruitment start date
Recruitment end date
Countries of recruitment
Trial participating centre
University of Birmingham
Hull and East Yorkshire Hospitals NHS Trust (UK)
Research & Development Department
2nd Floor Daisy Building
Castle Hill Hospital
Efficacy and Mechanism Evaluation Programme
NIHR Efficacy and Mechanism Evaluation Programme, EME
Funding Body Type
Funding Body Subtype
Results and Publications
Publication and dissemination plan
Planned publication in a high-impact peer reviewed journal.
IPD sharing statement
The data sharing plans for the current study are unknown and will be made available at a later date.
Intention to publish date
Participant level data
To be made available at a later date
Results - basic reporting
2016 protocol in: https://www.ncbi.nlm.nih.gov/pubmed/26429974