Renin–Angiotensin System

Inhibition in Advanced
CKD
 RAS Inhibitors in Mild to Moderate CKD
1. Reduce blood pressure
2. Slow decline in eGFR
3. Decrease proteinuria
4. Delay progression to advanced CKD (Stage 4 or 5)
5. Associated with improved quality of life and reduced risks
Lewis EJ, et al. 2001; Lewis EJ, et al. 1993; Brenner BM, et al. 2001; Remuzzi G, et al, 2004; Hou FF, et al. 2006.

• Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851-60.
• Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensinconverting–enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329: 1456-62.
• Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-9.
• Remuzzi G, Chiurchiu C, Ruggenenti P. Proteinuria predicting outcome in renal disease: nondiabetic nephropathies (REIN). Kidney Int Suppl 2004;66:Suppl 92:S90- S96.
• Hou FF, Zhang X, Zhang GH, et al. Efficacy and safety of benazepril for advanced chronic renal insufficiency. N Engl J Med 2006;354:131-40.
 Increased risks: cardiovascular
Advanced Impaired quality of
events, renal-replacement therapy,
CKD life
death

Neovius M, et al, 2014. CKD Prognosis Consortium, 2010; Gansevoort RT, et al. 2011; Landray MJ, et al. 2010; Quinn MP, et al. 2011.

Benefits of RAS inhibitors in

advanced stages

Little evidence
Quinn MP, et al. 2011.

• Neovius M, Jacobson SH, Eriksson JK, Elinder C-G, Hylander B. Mortality in chronic kidney disease and renal replacement therapy: a population-based cohort study. BMJ Open 2014;4(2):e004251.
• Chronic Kidney Disease Prognosis Consortium. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 2010; 375:2073-81.
• Gansevoort RT, Matsushita K, van der Velde M, et al. Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes: a collaborative meta-analysis of general and high-risk population cohorts. Kidney Int 2011;80: 93-104.
• Landray MJ, Emberson JR, Blackwell L, et al. Prediction of ESRD and death among people with CKD: the Chronic Renal Impairment in Birmingham (CRIB) prospective cohort study. Am J Kidney Dis 2010;56:1082-94.
• Quinn MP, Cardwell CR, Kee F, et al. The finding of reduced estimated glomerular filtration rate is associated with increased mortality in a large UK population. Nephrol Dial Transplant 2011;26: 875-80.
 This STOP-ACEi Trial
01 multicenter, randomized, open-label

02 patients with advanced and progressive CKD

the discontinuation of RAS inhibitors would increase or

03 stabilize the eGFR
RESULTS
Trial Design and Oversight
Funding: National Institute for Health Research and the Medical Research
Council

Trial Coordination: Birmingham Clinical Trials Unit

Oversight • Independent Steering Committee:

Committees: members unaware of group assignments.

• Data and Safety Monitoring Committee:

Monitored in an unblinded manner.
 Design and Authorship
01 Trial designed: first, fifth, and last authors.

02 Fourth author : adopting cardiovascular outcomes.

First author : initial draft

03 All coauthors : editing.
INCLUSION
• Adults (≥18 years).
• CKD Stage: Stage 4 or 5
• Not receiving dialysis or undergone kidney transplantation.
• eGFR Decline: >2 ml per minute per 1.73 m² per year in the previous 2
years.
• Treatment: Receiving ACE inhibitor, angiotensin-receptor blocker, or both
for >6 months.
EXCLUSION
• Uncontrolled hypertension.
• History of myocardial infarction or stroke within the previous 3
months.
Randomization
Ratio: • randomly assigned in a 1:1 ratio.

Method: • centralized internet-based system.

Minimization • ensure balance between the two groups

Technique
 TREATMENT
Discontinuation Group: Continuation Group:

Any guideline-recommended RAS inhibitor agent and dose.

antihypertensive agent (excluding RAS
inhibitors) Could combine it with others
(NICE 2019)

Target Blood Pressure: 140/85 mm Hg or lower.

(NICE, 2008; NICE 2019)

Follow Up: Every 3 months post-randomization for 3 years.

• National Institute for Health and Care Excellence (NICE). Chronic kidney disease: early identification and management of chronic kidney disease in adults in primary and secondary care. Clinical guideline CG73. September 2008 (https:// www.nice.org.uk/guidance/cg73).
• National Institute for Health and Care Excellence (NICE). Hypertension in adults: diagnosis and management. NICE guideline NG136. August 2019 (https://www .nice.org.uk/guidance/ng136).
 OUTCOMES
Primary Outcome: Secondary Outcome:

• eGFR at 3 Years: • Time until Development of ESKD

• MDRD175 four-variable • Composite Outcome
equation. • Hospitalization
(Al-Maqbali and Mula-Abed, 2014)
• Cystatin C and blood pressure.
• Quality of life
• Exercise capacity
• Cardiovascular events and death.
• Al-Maqbali SRS, Mula-Abed W-AS. Comparison between Three Different Equations for the Estimation of Glomerular Filtration Rate in Omani Patients with Type 2 Diabetes Mellitus. Sultan Qaboos Univ Med J 2014;14(2):e197-e203
Statistical Analysis
Sample Size Alpha level: 0.05  20% loss to follow-up.

Primary Outcome Secondary Outcome Analysis:

Analysis:
Continuous outcomes
• Similar with primary
Repeated-measures,
mixed-effects linear
regression model. Time-to-event
• Cox proportional-hazards
model.
Categorical outcomes
• Poisson regression model for
relative risk.
Safety outcomes
• percentages.
 Subgroup Analyses:

primary outcome based on Software

minimization variables.
SAS software, version 9.4
(SAS Institute).

Stata software, version 17

(StataCorp).
RESULTS
Randomization and
Outcomes
 Treatment Adherence

First 3 • Discontinuation Group: 94.2% adherence (180 patients).

• Continuation Group: 94.2% adherence (179 patients).
Months:

• Discontinuation Group: 88% adherence (50 patients).

3 Years: • Continuation Group: 77% adherence (53 patients).
 PRIMARY OUTCOMES
eGFR at 3 Years:
• Discontinuation Group: 12.6±0.7 ml/min/1.73 m²
• Continuation Group: 13.3±0.6 ml/min/1.73 m²
Difference: -0.7 (95% CI: -2.5 to 1.0; P=0.42)

Negative value favorable outcome for the continuation group.

Sensitivity Analyses Similar results, Consistent outcomes

 SECONDARY OUTCOMES
ESKD or Renal-Replacement Therapy (3 Years):
Adjusted Hazard Ratio: 1.28 (95% CI, 0.99 to 1.65)

Renal-Replacement Therapy or >50% eGFR Decrease (3 Years):

Adjusted Relative Risk: 1.07 (95% CI, 0.94 to 1.22)
 Deaths (3 Years):
Hazard Ratio: 0.85 (95% CI, 0.46 to 1.57)

6-Minute Walk Test (3 Years):

Adjusted Mean Difference: -18 m (95% CI, -57 to 22)

Urinary Protein  Creatinine Ratio (3 Years):

Adjusted Mean Difference: -9 (95% CI, -673 to 655)
Secondary Outcome
 ADVERSE EVENTS
Total Serious Adverse Events: 490 events

Trial-Group Related Adverse Events: 21 events

Suspected Serious Adverse Reaction: approximately 15

months after randomization.
Discussion
 Primary Outcome (eGFR): No clinically relevant increase in eGFR observed.

ESKD or RRT (3 Years): Similar occurrences in both groups

Cardiovascular Events and Death (3

Comparable frequencies
Years):

Blood Pressure and Proteinuria: Initial increase in discontinuation group

Quality of Life and Exercise

No material differences
Capacity:
 Inconsistent Previous Trials of RAS inhibitors

Post Hoc potential benefits of RAS inhibitors in advanced CKD

Analyses:

Observational discontinuation  reduced the risk of progression to ESKD.

Study:
Ahmed AK, et al, 2010.

Large discontinuation  risk of progression to ESKD.

Observational
Fu EL, et al, 2021.

• Ahmed AK, Kamath NS, El Kossi M, El Nahas AM. The impact of stopping inhibitors of the renin-angiotensin system in patients with advanced chronic kidney disease. Nephrol Dial Transplant 2010;25:3977-3982.
• Fu EL, Evans M, Clase CM, et al. Stopping renin-angiotensin system inhibitors in patients with advanced CKD and risk of adverse outcomes: a nationwide study. J Am Soc Nephrol 2021;32:424-35.
 rate of decline in
good predictor of the development of ESKD
the eGFR
Levey AS, et al, 2020.

3 years delay
preservation of the eGFR slope >0.75 ml/min/1.73 m2 year
progression
Inker LA,et al,2019.

RAS inhibitors slow the decline in eGFR in mild or moderate SKD

Maschio G, et al, 1996.

This Trial:
these drugs may not be as helpful in patients with advanced and progressive CKD

• Levey AS, Gansevoort RT, Coresh J, et al. Change in albuminuria and GFR as end points for clinical trials in early stages of CKD: a scientific workshop sponsored by the National Kidney Foundation in collaboration with the US Food and
Drug Administration and European Medicines Agency. Am J Kidney Dis 2020;75: 84-104.
• Inker LA, Heerspink HJL, Tighiouart H, et al. GFR slope as a surrogate end point for kidney disease progression in clinical trials: a meta-analysis of treatment effects of randomised controlled trials. J Am Soc Nephrol 2019;30:1735-45.
• Maschio G, Alberti D, Janin G, et al. Effect of the angiotensin-convertingenzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med 1996;334:939-45.
 discontinuing RAS Increased major cardiovascular events and death
inhibitors

Fu et al.,2021

increased cardiovascular risk and death

Stopping RAS
inhibitors
did not reduce the need for RRT
Qiao et al, 2020

This Trial:
 Need conduct a larger randomized trial to investigate cardiovascular safety.

● Fu EL, Evans M, Clase CM, et al. Stopping renin-angiotensin system inhibitors in patients with advanced CKD and risk of adverse outcomes: a nationwide study. J Am Soc Nephrol 2021;32:424-35.
● Qiao Y, Shin J-I, Chen TK, et al. Association between renin-angiotensin system blockade discontinuation and all-cause mortality among persons with low estimated glomerular filtration rate. JAMA
Intern Med 2020;180:718-26.
LIMITATION
Limits generalizability to other racial or ethnic groups.

Failure to strictly adhere to randomly assigned management strategy.

Open-label nature

Limited to patients receiving RAS inhibitors at randomization.

Not generalize to patients with higher levels of proteinuria (>2655).

CONCLUSION
discontinuation of RAS inhibitors in patients with advanced and progressive
chronic kidney disease did not lead to a clinically relevant change in the eGFR or
a between-group difference in the long-term rate of decline in the eGFR.
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