Discontinuing RAS Inhibitors Does Not Decrease Long-Term eGFR

Sunil Bhandari

The discontinuation of either angiotensin-converting-enzyme inhibitors (ACEi) to angiotensin-receptor blockers (ARBs) does not slow the progression of advanced chronic kidney disease (CKD).

A team, led by Sunil Bhandari, Hull University Teaching Hospitals NHS Trust, assessed whether discontinuation of ACEi or ARBs could slow the progression of disease in patients with advanced CKD.

The data was presented as a late-breaking abstract during the 2022 American Society of Nephrology (ASN) Annual Meeting in Orlando.

ACEi and ARBs

Both ACEi and ARB can slow the progression of mild to moderate CKD. However, some smaller studies have found delayed progression in patients with advanced disease after the discontinuation of ACEi or ARB.

In the open label, phase 2, multicenter, randomized controlled STOP-ACEi trial, the investigators examined adult patients with stage 4-5 CKD treated with ACEi and/or ARB from 37 UK renal centers between July 11, 2014 and June 19, 2018. Patients were randomized to either the discontinuation or experimental arm or the continuation or control arm. Each participant was stratified based on age, baseline eGFR, diabetes, blood pressure, and proteinuria.

The investigators sought primary endpoints of kidney function (MDRD 4-variable eGFR) at year 3. This was analyzed using a linear regression model, with sensitivity analysis including the use of pattern mixture and joint models.

The team also sought secondary outcome measures, including the number starting renal replacement therapy and/or sustaining a greater than 50% decline in eGFR, quality of life/wellbeing, hospitalization rates, and safety measures such as cardiovascular event rates and mortality.

The Patients

Overall, there were 411 patients in the study, with a median age of 63.4 years. The median baseline creatinine level was 299 99 (243-367) µmol/L, while the median eGFR was 18 (14-22)mL/min/1.73m² and the median urinary protein:creatinine ratio was 115mg/mmol (28-248). The comorbidities of the participants included hypertension (71%), atrial fibrillation (45%), ischemic heart disease (14%), a previous history of stroke (6%), peripheral vascular disease (5%), and heart failure (4%).

The least-squares mean eGFR at the 3 year mark 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% CI, −2.5 to 1.0; P = 0.42). There was a negative value favoring the outcome in the continuation group.

There was no heterogeneity in outcomes based on the prespecified subgroups. In addition, 62% (n = 126) of participants in the discontinuation group and 56% (n = 115) of participants in the continuation group had end-stage kidney disease (ESKD) or the initiation of renal-replacement therapy (HR, 1.28; 95% CI, 0.99-1.65).

For safety, the reported adverse events were similar in both groups for cardiovascular events (108 vs 88) and deaths (20 vs 22).

“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,” the authors wrote.

The study, “Multi-Center Randomized Controlled Trial of Angiotensin Converting Enzyme Inhibitor (ACEi)/Angiotensin Receptor Blocker (ARB) Withdrawal in Advanced Kidney Disease: The STOP-ACEi Trial,” was published online by ASN.