Study sheds new light on role of RAS inhibitors in advanced CKD

Study sheds new light on role of RAS inhibitors in advanced CKD

ORLANDO, Fla. – Treatment with a renin-angiotensin system (RAS) blocker is widely accepted as standard practice for slowing the progression of chronic kidney disease (CKD), but data is inconsistent about whether there is a benefit in continuing RAS inhibition when patients develop advanced CKD, defined as an estimated glomerular filtration rate (eGFR) of less than 30 mL/min/1.73 m2.

Now, in STOP ACEi, a new multicenter randomized trial of 411 patients, continued treatment with a RAS inhibitor in adults with advanced and progressive CKD did not cause clinically relevant changes in kidney function, or rate of long-term decline in renal function, relative to treatment discontinuation, for 3 years.

Individuals who continued RAS inhibitor therapy did not develop significant or clinically relevant decreases in eGFR, the study’s primary endpoint, both overall and in several subgroups predefined compared to those who stopped treatment, said Sunil Bhandari, MBChB, PhD, and associates, who presented the research in a poster at Kidney Week 2022, hosted by the American Society of Nephrology.

I hope these results will reassure clinicians to pursue ACE inhibitors or ARBs” in patients with advanced CKD, “with their known beneficial cardiovascular effects,” Bhandari said. Medscape Medical News.

The results were published simultaneously in the New England Journal of Medicine.

Similar eGFR levels after 3 years

Although it is clear that in patients with mild to moderate CKD, treatment with an RAS inhibitor, which includes angiotensin-converting enzyme (ACE) inhibitors and receptor antagonists angiotensin (ARA), reduces blood pressure, slows eGFR decline, reduces proteinuria, and delays progression to advanced CKD, there is little evidence that the use of RAS inhibitors benefits patients with angiotensin ‘Advanced IRC.

Data from previous trials have been inconsistent on whether the use of RAS inhibitors is nephroprotective in patients with advanced CKD, says Bhandari, a nephrologist and professor at Hull York Medical School, Hull, UK, and his colleagues.

“Current guidelines do not provide specific advice on continuing or discontinuing ACE inhibitors or ARBs for advanced chronic kidney disease,” they also note.

They therefore decided to assess whether stopping ACE/ARB inhibitors could slow the progression of CKD in patients with advanced CKD.

Three years after 206 study participants discontinued RAS inhibitor therapy, the least-squares mean eGFR was 12.6 mL/min/1.73 m2 in the stop group and 13.3 mL/min/1.73m2 in the 205 patients in the continuation group, the difference was not significant.

In addition to the primary outcome, 62% of patients who discontinued RAS inhibitor treatment and 56% of those who continued developed end-stage renal disease or required renal replacement therapy, resulting in by an adjusted relative risk of 1.28 for this outcome among those who quit versus those who continued, which was just short of significance (95% CI, 0.99, 1.65).

The two study groups also showed no significant difference in the 3-year incidence of hospitalizations for any reason, cardiovascular events, or deaths. The two groups also showed no significant difference in various areas of quality of life and no difference in serious adverse effects.

Participants had an eGFR less than 30 mL/min/1.73 m2

The study took place in 39 UK centers in 2014-2019. Investigators recruited adults with an eGFR less than 30 mL/min/1.73 m2 who were not on dialysis and had not received a kidney transplant. In addition, all enrolled patients were required to have an annual decline in eGFR of greater than 2 mL/min/1.73 m2 within the previous 2 years and must have been on treatment with at least one RAS inhibitor for more than 6 months.

The randomization protocol ensured a balanced distribution of subjects between the two arms of the study according to age, eGFR, presence of diabetes and level of proteinuria, among other factors. The study design also required participants to maintain blood pressure no higher than 140/85 mmHg.

Those who discontinued RAS inhibitor therapy could receive any guideline-recommended antihypertensive agent that was not a RAS inhibitor, although the addition of a RAS inhibitor was allowed as a last resort.

People in the maintenance group could receive whatever additional antihypertensive agents their treating clinicians deemed necessary to maintain target blood pressure.

The registered population had a median age of 63 years and 68% were male. Their mean eGFR at baseline was 18 mL/min/1.73 m2and 118 (29%) had an eGFR less than 15 mL/min/1.73 m2. Their median proteinuria level was 115 mg/mmol (about 1018 mg/g). Diabetes was prevalent in 37% of participants and 58% of participants were taking at least three antihypertensive medications at entry.

Among the limitations of the study, the researchers cited the open-label design, which may have affected clinical care and the counting of subjective parameters, including quality of life and exercise capacity. Also, because the study recruited people who were taking a RAS inhibitor at the time of randomization, it did not include people who had previously stopped these agents.

Continue RAS inhibitors in advanced CKD for best results

Bhandari and colleagues note that in a large observational trial published in January 2021, Swedish researchers found an increased incidence of major cardiovascular events and death in patients with advanced CKD who had stopped RAS inhibitors, as reported Medscape Medical News.

But they observe: “Our trial was underpowered to study the effect of stopping RAS inhibitors on cardiovascular events or mortality. There is little reason to conduct a larger randomized trial to study cardiovascular safety. »

“Our results do not support the hypothesis that discontinuation of RAS inhibitors in patients with advanced and progressive chronic kidney disease would improve kidney function, quality of life, or exercise capacity.”

“The results of this trial will inform future clinical practice worldwide and guideline recommendations,” they conclude.

STOP ACEi has received no commercial funding. Bhandari has did not report any relevant financial relationships.

N English J med. Published online November 3, 2022. Summary

Kidney Week 2022. Abstract TH-PO966. Presented November 3, 2022.

Mitchel L. Zoler is a reporter for Medscape and MDedge based in the Philadelphia area. @mitchelzoler

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