Stop RAS Inhibitors in Advanced CKD? STOP ACEi Trial Sheds Some Light

Ditching renin-angiotensin system (RAS) inhibitors in advanced chronic kidney disease (CKD) didn't help to slow kidney decline, according to the STOP ACEi trial.

Among patients with a baseline eGFR below 30 mL/min/1.73 m², eGFR level at 3 years was 13.3±0.6 mL/min/1.73 m² for those who continued on RAS inhibitors versus 12.6±0.7 mL/min/1.73 m² for those who discontinued them -- missing the trial's primary endpoint (P=0.42), reported Sunil Bhandari, PhD, of Hull University Teaching Hospitals NHS Trust in England, and colleagues.

These findings were presented at the American Society of Nephrology's Kidney Week and simultaneously published in the New England Journal of Medicine.

Furthermore, when Bhandari's group isolated several subgroups -- diabetes status (type 1, type 2, or none), mean arterial pressure (<100 mm Hg, 100+ mm Hg), age (<65, 65+), protein:creatinine ratio (<885, 885+), and baseline eGFR (<15, 15+) -- they found no significant differences in eGFR after quitting or continuing RAS inhibitors.

"Our findings do not support the hypothesis that the discontinuation of RAS inhibitors in patients with advanced and progressive chronic kidney disease would improve kidney function, quality of life, or exercise capacity," Bhandari's group concluded.

While the use of RAS inhibitors, like angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers, is standard practice in patients with mild or moderate CKD in order to lower blood pressure, slow eGFR decline, and reduce proteinuria, Bhandari's group said there was little prior evidence backing their benefits in advanced CKD.

"Current guidelines do not provide specific advice on whether to continue or stop ACE inhibitors or angiotensin-receptor blockers for advanced chronic kidney disease," they pointed out.

They also found there wasn't a significant difference seen between the two treatment paths when it came to progression to end-stage kidney disease (ESKD) or initiation of renal-replacement therapy -- one of the trial's secondary outcomes -- which occurred in 62% of those who discontinued RAS inhibitors versus 56% of those who continued them (adjusted HR 1.28, 95% CI 0.99-1.65).

However, there were still "numerically more" RAS inhibitor discontinuers who progressed to ESKD. Because of this, the group suggested looking at this again in a larger trial with more participants.

In other secondary outcomes, there were no differences in the numbers of patients who underwent renal-replacement therapy or those who experienced more than a 50% decline in eGFR (68% of discontinuation group vs 63% of continuation group).

A total of 20 deaths occurred in the discontinuation group, while 22 occurred in the continuation group. Likewise, there were similar numbers of all-cause hospitalizations (414 and 413, respectively) and number of cardiovascular events (108 and 88).

Several other secondary outcomes were also similar between the groups at 3 years, including:

• Hemoglobin level
• Distance covered during 6-minute walking test
• Quality of life
• Number of antihypertensives prescribed during trial
• Blood pressure

However, the discontinuation group did see a slight bump in protein level during the first year. This group also had higher systolic and diastolic blood pressure in the first 15 months, but this dropped down by the end of the trial. These early blood pressure changes were considered adverse events.

A total of 490 serious adverse events occurred during the trial, with no significant differences in cardiovascular, vascular, and heart failure events between the two groups. One patient in the discontinuation group experienced a possible transient ischemic attack 15 months into the trial.

The 39-center U.K.-based trial randomized 411 adults: 206 to discontinue RAS inhibitors and 205 to continue. All participants had stage 4 or 5 CKD, were not on dialysis, had not undergone kidney transplantation, and had experienced an eGFR drop of more than 2 mL/min/1.73 m² per year in the 2 years prior to the study. Treatment with an ACE inhibitor, an angiotensin-receptor blocker, or both for more than 6 months prior to the study was also an eligibility requirement.

About 85% of participants were white, median age was 63, and 68% were men. The most common sources of CKD were glomerulonephritis, hereditary disease (including autosomal dominant polycystic kidney disease), renal vascular disease or hypertension, diabetic nephropathy, and other or unknown causes.

Comment