Stopping RAS Inhibition Therapy Increases Risk of Cardiovascular Events

Edouard L. Fu, BSc

While it is not currently known whether stopping renin-angiotensin system (RAS) inhibitor therapy in patients with advanced chronic kidney disease (CKD) impacts overall outcomes, new research suggests stopping this therapy increases the risk of adverse events.

A team, led by Edouard L. Fu, BSc, Department of Clinical Epidemiology, Leiden University Medical Center, examined patients listed on the Swedish Renal Registry who were referred to nephrologist care between 2007-2017 and developed advanced CKD (eGFR<30 ml/min per 1.73 m²) while on RAS inhibitor therapy.

Study Methods

Overall, they used target trial emulation techniques on the basis of cloning, censoring, and weighting. Using these methods, the research team compared the risks of stopping within 6 months and remaining off treatment with continuing RAS inhibitor therapy, including the risks of subsequent 5-year all-cause mortality, major adverse cardiovascular events, and inhibition of kidney replacement therapy.

The investigators identified 10,254 patients prevalently using RAS inhibitor therapies with new-onset eGFR <30 ml/min per 1.73 m². The median age of the patient population was 72 years old and 64% of the patients were male.

However, 1553 individuals (15%) stopped RAS inhibitor therapy within 6 months.

The median eGFR was 23 ml/min per 1.73 m².

The Value of RAS Therapy

Stopping RAS therapy was linked to a higher absolute 5-year risk of death when compared to continuing RAS inhibition (40.9% versus 54.5%), as well as the risk of major adverse cardiovascular events (47.6% versus 59.5%).

This patient population also had a lower risk of kidney replacement therapy (36.1% versus 27.9%). These 3 statistics correspond to absolute risk differences of 13.6 events per 100 patients, 11.9 events per 100 patients, and -8.3 events per 100 patients, respectively.

The results were also consistent whether patients stopped RAS inhibition at higher or lower eGFR, across prespecified subgroups, after adjustment and stratification for albuminuria and potassium, and when modeling RAS inhibition as a time-dependent exposure using a marginal structural model.

“In this nationwide observational study of people with advanced CKD, stopping RAS inhibition was associated with higher absolute risks of mortality and major adverse cardiovascular events, but also with a lower absolute risk of initiating [kidney replacement therapy],” the authors wrote.

A Better Understanding of Chronic Kidney Disease

Recent single center studies have suggested improved kidney function after stopping RAS inhibition, as well as a possible delay in initiating kidney replacement therapy. However, there has been a lack of large prospective studies assessing cardiovascular and kidney outcomes.

Recently, investigators were able to identify high-risk subgroups of CKD progression.

A team, led by Amanda H. Anderson, PhD, MPH, Department of Epidemiology Tulane University School of Public Health and Tropical Medicine, identified 30 risk factors for chronic kidney disease progression across sociodemographic, behavioral, clinical, and biochemical domains at baseline.

For patients without and with diabetes the mean eGFR was -1.4 and -2.7 mL/min/1.73m²/year, respectively.

The study, “Stopping Renin-Angiotensin System Inhibitors in Patients with Advanced CKD and Risk of Adverse Outcomes: A Nationwide Study,” was published online in the Journal of the American Society of Nephrology.