Stopping RAS inhibitors does not slow eGFR decline in advanced CKD

In patients with advanced chronic kidney disease (CKD), discontinuing renin–angiotensin system (RAS) inhibitor therapy does not slow down decline in estimated glomerular filtration rate (eGFR), a recent trial showed.

“Our STOP-ACEi trial excluded a clinically relevant improvement in eGFR after stopping RAS inhibitors in patients with advanced CKD, overall or in prespecified subgroups by age, severity of CKD, diabetes, proteinuria, or blood pressure (BP),” said study author Professor Sunil Bhandari from the Hull University Teaching Hospitals NHS Trust and Hull York Medical School, Hull, UK.

“If indicated for the treatment of hypertension, proteinuria, or cardiovascular (CV) disease, RAS inhibitors should not be stopped just because eGFR is low,” he said.

Participants in this multicentre, UK-based, open-label trial were 411 adults (median age 63 years, 68 percent male, 15 percent non-White) with advanced and progressive stage 4–5 CKD (eGFR ≤30 mL/min/1.73 m²* [median 18 mL/min/1.73 m²]) and BP ≤160/90 mm Hg who were on RAS inhibitors (ACE** inhibitors or ARBs**) for >6 months. They were randomized 1:1 to either continue or discontinue RAS inhibitors. Other guideline-recommended antihypertensive medications were allowed in the group that discontinued RAS inhibitors. Target BP was ≤140/85 mm Hg. Patients were followed up for a median 3 years.

Thirty-seven percent of patients had diabetes, 21 percent diabetic nephropathy, 17 percent hypertensive or renovascular nephropathy, and 18 percent glomerulonephritis. Sixty-five and 40 percent were on statins and bicarbonate supplements, respectively.

At 3 years, eGFR did not significantly differ between patients who discontinued or continued RAS inhibitors (least-squares mean 12.6 vs 13.3 mL/min/1.73 m²; difference, –0.7 mL/min/1.73 m², 95 percent confidence interval [CI], –2.5 to 1.0; p=0.42). [Kidney Week 2022, abstract TH-PO966; N Engl J Med 2022;doi:10.1056/NEJMoa2210639]

The outcomes were consistent in the prespecified subgroups analysed.

At 3 years, the composite of end-stage kidney disease (ESKD) or requirement for renal-replacement therapy was documented in 62 and 56 percent of patients who discontinued or continued RAS inhibitors, respectively (adjusted hazard ratio [adjHR], 1.28, 95 percent CI, 0.99–1.65). A similar proportion of patients who discontinued or continued RAS inhibitors underwent renal-replacement therapy (including those who developed ESKD) or experienced a >50-percent decrease in eGFR (68 percent vs 63 percent (adjusted relative risk, 1.07, 95 percent CI, 0.94–1.22).

All-cause hospitalization rate was similar in patients who discontinued and continued RAS inhibitors (414 and 413 events, respectively), as was CV event rate (108 and 88 events, respectively). There were 20 and 22 deaths, respectively, among those who discontinued and continued RAS inhibitors (HR, 0.85, 95 percent CI, 0.46–1.57).

BP levels were higher among those who discontinued vs continued RAS inhibitors in the first 15 months of the trial and were then comparable between groups. A similar finding was noted with proteinuria incidence in the first year of the trial. The comparable levels between groups after the first year could be due to initiation of non-RAS inhibitor antihypertensive agents, said the authors.

Exercise capacity at 3 years, according to distance covered during the 6-minute walk test, was similar between those who discontinued and continued RAS inhibitors (least-squares mean 394 vs 412 m). Quality of life (QoL) did not significantly differ between groups.

Of the 490 serious adverse events documented, 21 were possibly attributable to trial group, with a comparable number of patients affected in each group. The incidence of serious adverse CV, vascular, and heart failure events was comparable between groups. One patient who discontinued RAS inhibitor therapy experienced a possible transient ischaemic attack.

According to the authors, RAS inhibitors have been known to slow eGFR decline in patients with mild or moderate CKD. “[O]ur findings are consistent with the possibility that these drugs may not be as helpful in patients with advanced and progressive CKD,” they pointed out.

“Our findings do not support the hypothesis that the discontinuation of RAS inhibitors in patients with advanced and progressive CKD would improve kidney function, QoL, or exercise capacity,” said Bhandari and co-authors.