Patients with chronic kidney disease (CKD) who discontinue renin-angiotensin system (RAS) inhibitors have significantly higher risks for death and end-stage kidney disease (ESKD), according to new research.

“While we do not know definitively whether the acute decline in eGFR [estimated glomerular filtration rate] triggered clinicians to stop the RAS inhibitors, our findings suggest that there is benefit to continuing these agents and no signal of harm, even when declines in eGFR were more than 30%,” the authors wrote.

“These findings highlight the potential risks of discontinuing RAS inhibitor therapy when small declines in kidney function following their initiation occur,” they added.

RAS inhibitors, including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, are well established for slowing CKD progression. However, up to 20% of patients experience an early decline in eGFR after starting therapy.

Guidelines recommend tolerating increases in serum creatinine of up to 30% after initiation of RAS inhibitors. Despite this, clinicians frequently discontinue these otherwise beneficial drugs in response to smaller declines in eGFR.

The study was published in JAMA Network Open.

Target Trial Emulation Approach

To evaluate the impact of RAS inhibitor discontinuation, first author Elaine Ku, MD, Division of Nephrology, Departments of Medicine and Pediatrics, University of California, San Francisco, and colleagues conducted a retrospective cohort using a target trial emulation approach, which uses observational data to mimic a randomized controlled trial.

The analysis included 4233 patients with CKD from the Manitoba Centre for Health Policy database (2008-2021) who experienced a more than 15% decline in eGFR within 90 days of starting RAS inhibitors.

Using propensity score matching (2:1), patients who discontinued therapy drugs (defined as not having an active prescription between days 90 and 180 after the initial prescription; 33.3%) were compared with those who continued (66.6%). Groups were balanced for key factors including age, sex, baseline eGFR, comorbidities, and concomitant medications. Patients with baseline potassium levels > 5.5 mEq/L were excluded to minimize confounding from hyperkalemia risk.

Patients had a mean age of 64.6 years, and 51.1% were male. At baseline, 24.5% had stage G3 to G5 CKD, 17.6% had congestive heart failure, and 20.9% had diabetes.

Over a mean follow-up of 4.7 years, 30.9% of patients died, 6.0% developed ESKD, 35.1% experienced major adverse cardiac events (MACE), and 14.0% had acute kidney injury.

Discontinuation of RAS inhibitors was associated with a significantly higher risk for all-cause mortality (hazard ratio [HR], 1.23; P = .003) and ESKD (HR, 1.74; P = .005) than continued use. No significant differences were observed between the groups for the risk for MACE (HR, 1.13) or acute kidney injury (HR, 1.11).

Subgroup analyses showed a large effect size between RAS inhibitor discontinuation and ESKD risk among patients with a history of diabetes or CKD, although the overall results were similar among patients with CKD, heart failure, or diabetes at baseline.

RAS inhibitor discontinuation was not associated with an increased risk for cataract surgery (HR, 1.10), and the findings were consistent when the start of the eGFR decline was changed to 150 days after initiation.

Notably, patients with CKD at baseline were more likely to have their RAS inhibitors discontinued.

“We speculate that clinicians may have been more concerned about the loss of eGFR with RAS inhibitor initiation in patients who already had a low eGFR,” the authors wrote.

The findings align with observations from studies with SGLT2 inhibitors, in which early declines in eGFR are also considered benign, and guidelines similarly recommend not reacting to these changes.

Clinical Context and Caveats

Senior author Mark J. Sarnak, MD, MS, Division of Nephrology, Department of Medicine, Tufts Medical Center, Boston, noted that reasons for discontinuation could not be determined.

“In our study, 33% with decline in eGFR stopped the RAS inhibitors, but we do not know if the decline in eGFR was the reason for stopping,” Sarnak told Medscape Medical News.

He emphasized that discontinuation may still be appropriate in some clinical situations.

“If the eGFR decline is high or if there is associated hyperkalemia, then RAS inhibitors may need to be discontinued,” he said.

Moving forward, Sarnak added, better understanding of why RAS inhibitors are being discontinued will be important, as well as improving clinician education.

Expert Perspective

Commenting on the study, Richard Lafayette, MD, a professor of medicine (nephrology) at the Stanford University Medical Center and founder and director of the Stanford Glomerular Disease Center, both in California, said the findings are consistent with the known benefits of RAS inhibitors.

“We should generally advocate for ongoing RAS inhibitor use in patients at risk for progressive CKD,” he told Medscape Medical News. “Rising creatinine is expected, and whenever possible, RAS inhibitors should be retried if there are side effects.”

However, he cautioned that the study was limited by significant confounding despite the patients being well balanced.

“We cannot begin to know the individual decisions of why some patients were restarted and some were not,” he said.

He added that kidney function recovery after discontinuation was not captured and may have influenced both treatment decisions and outcomes.

Still, “observational studies like this suggest meaningful benefits,” he concluded.

“Patients with CKD should be aggressively treated with RAS inhibitors, and most who develop significant reductions in GFR after starting, and even those with hyperkalemia, can frequently be restarted,” Lafayette said.

“Practitioners should not be swayed by small, non-progressive, not clinically significant or unexpected responses to RAS inhibitors.”

Findings Should Give Reassurance

Sunil Bhandari, MB ChB, PhD, vice president of the Royal College of Physicians of Edinburgh in Edinburgh, Scotland, and honorary professor and tra nsplant physician at Hull University Teaching Hospitals NHS Trust and HYMS in Hull, England, noted that the findings align with those observed in the STOP ACEi trial, on which he was first author.

“In the STOP ACEi trial, we surveyed clinicians in the United Kingdom to see if they would stop or continue RAS inhibitors in advanced CKD and found almost a 50% split — hence, equipoise based on physician preference,” Bhandari told Medscape Medical News.

“This still persists, with the view that one can delay the need for dialysis,” he said. “As we said in the STOP ACEi trial, the benefit of continuing was to maintain cardiovascular protection.”

Overall, the new findings, although not from a randomized controlled trial, “are as close as possible using this novel [target trial emulation] methodology,” Bhandari said. “Hopefully it will give further reassurance to clinicians.”

Sarnak reported receiving personal fees from Akebia and an honorarium from Boehringer Ingelheim outside the submitted work; his spouse is an employee of Eli Lilly. Lafayette and Bhandari had no disclosures to report.