Don't Routinely Stop RAS Inhibitors in Advanced Kidney Disease

Marlene Busko

January 07, 2021

A large Swedish observational study suggests that patients with chronic kidney disease (CKD) who develop advanced illness should continue taking a renin-angiotensin system (RAS) inhibitor — an angiotensin receptor blocker (ARB) or angiotensin-converting enzyme (ACE) inhibitor.

Specifically, among more than 10,000 such patients, those who continued versus stopped taking a RAS inhibitor had a 13.6% lower risk of death and an 11.9% lower risk of a major adverse cardiovascular event (MACE; a composite of death, myocardial infarction, and cerebrovascular events), albeit with an 8.3% greater risk of needing to start renal replacement therapy (dialysis or kidney transplant), during a 5-year follow-up.

"Our study is the largest to date investigating the clinical consequences associated with this common clinical issue, whether to continue or stop [RAS inhibitors] in patients with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2," Edouard L. Fu and colleagues write in their article published December 29 in the Journal of the American Society of Nephrology.

The findings "caution against routine discontinuation" of RAS inhibitors in such patients and suggest that risks of cardiovascular events or death versus kidney replacement therapy be considered in decisions about stopping the drug treatment, summarize Fu, an MD/PhD candidate in clinical epidemiology at Leiden University Medical Center, the Netherlands, and coauthors.

"Until the ongoing [randomized] STOP-ACEi trial is completed," they conclude, "our analyses support current Kidney Disease Improving Global Outcomes [KDIGO] recommendations of not routinely stopping [RAS inhibitors] in people with advanced CKD."

Need for Individualized Treatment

Invited to comment, Matthew R. Weir, MD, University of Maryland, Baltimore, who is lead author of a 2018 review of the use of RAS blockade in advanced CKD, said clinicians commonly reduce or stop RAS inhibitors in those who develop advanced disease.

However, the current study suggests it is better for such patients to stay on treatment because they had better outcomes, he told Medscape Medical News in an email.

And Sunil Bhandari, MBChB, PhD, Hull York Medical School, UK, who is lead investigator of the STOP-ACEi trial, told Medscape Medical News that the study by Fu and colleagues "strengthens the argument for the [randomized] STOP-ACEi study, as we have been caught out with observational studies in the past."

STOP-ACEi is randomizing 410 participants with advanced (stage 4 or 5) progressive CKD receiving an ACE inhibitor, ARB, or both, to either discontinue all RAS inhibitor therapy (experimental group) or continue it (control group) on a 1:1 basis. The primary outcome is eGFR at 3 years. Secondary outcomes include the number of renal events, quality of life, hospitalization rates, and blood pressure. Safety will be assessed to ensure that treatment withdrawal does not cause excess harm or increase mortality or cardiovascular events such as heart failure, myocardial infarction, or stroke.

"We hope to have [STOP-ACEi] data lock by August 2021 and therefore present the data before the end of the year — COVID-19 depending," Bhandari added.

In the meantime, "treatment [should remain] individualized based on clinical circumstances and weighing up benefit versus risk," said Bhandari, which he and his colleagues also emphasized in a 2019 review of RAS inhibitors.

Clinical Conundrum in Advanced CKD: Patient Monitoring Is Key

RAS inhibitors are primarily used to treat hypertension and are also used for conditions such as heart failure and chronic kidney disease, independent of their effect on blood pressure.

They are a cornerstone for treating CKD with proteinuria, supported by trials that show they delay progression to advanced CKD, Fu and colleagues write.

However, few patients with advanced CKD were part of the pivotal trials of ACE inhibitors and ARBs, and there is little evidence to guide treatment decisions for patients who develop advanced CKD.

"Current guidelines [KDIGO], which are some 8 years old, recommend individualization of care for treatment and, where possible, continuation of RAS inhibitors in CKD," Bhandari noted, "but this remains a complex area with decisions based on clinician perception."

"Certainly, when I first started the STOP-ACEi study," he continued, "there were clinicians who felt the drugs should be discontinued while others [felt] that [they] should be continued in advanced CKD — hence the equipoise. I do not think this has changed."

Reasons for stopping RAS inhibitors, he noted, "usually include adverse events such as hyperkalemia and deterioration in renal function precipitating hospital admissions or low blood pressure."

"The key is monitoring [patients]," he added. For example, "The [UK] National Institute for Health and Care Excellence discusses 'sick day' rules: stop [RAS inhibitor therapy] temporarily when the patient is ill, say with diarrhea, as this may worsen renal function."

Bhandari also points to a 2017 study by Schmidt and colleagues in 122,363 patients who began RAS inhibitor therapy.

The findings showed higher rates of end-stage renal disease, myocardial infarction, heart failure, and death in those whose creatinine levels rose by 30% or more after starting treatment, and there were also worse outcomes to a lesser degree in patients who had a smaller increase in creatinine — all highlighting the need to closely monitor patients.

Registry Study of More Than 10,000 Patients

For the current study, Fu and colleagues identified 10,254 patients listed in the Swedish National Registry who were treated by a nephrologist and developed advanced CKD (eGFR < 30 mL/min/1.73m2) while taking RAS inhibitor therapy for at least a decade (2007-2017).

Patients were a mean age of 72 years and 36% were women.

A total of 15% (1553 patients) stopped therapy within 6 months of developing advanced CKD (median eGFR, 23 mL/min/1.73m2).

Patients who continued versus stopped therapy were less likely to die (40.9% vs 54.5%) or develop MACE (47.6% vs 59.5%), but more likely to need kidney replacement therapy (36.1% vs 27.9%), during a 5-year follow-up.

The results were similar in patients with a first-detected eGFR decrease of 20-30 mL/min/1.73m2 or < 20 mL/min/1.73m2.

Results were also similar across other subgroups, including those with albuminuria or elevated potassium (possible triggers for stopping or continuing RAS inhibitors).  

The investigators acknowledge that study limitations include a lack of information about physician prescribing behavior, patient frailty, and precise reasons for stopping RAS inhibitor therapy, as well as possible unknown confounders.

The study was supported by the Swedish Research Council, Swedish Heart and Lung Foundation, and Westman Charitable Foundation. Fu and the other authors, as well as Weir and Bhandari, have reported no relevant financial relationships.

J Am Soc Nephrol. Published online December 29, 2020. Abstract

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