Therapy With RAS Inhibitors in Advanced CKD

The use of renin-angiotensin system (RAS) inhibitors, including angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), in patients with mild-to-moderate chronic kidney disease (CKD) has been shown to reduce blood pressure, slow decline in estimated glomerular filtration rate (eGFR), reduce proteinuria, and delay progression to advanced CKD (stage 4 or 5).

Patients who progress to stage 4 or 5 CKD have impaired quality of life and an increased risk of renal replacement therapy (RRT), cardiovascular events, and death. However, according to Sunil Bhandari, PhD, and colleagues in the United Kingdom there are few data available on the benefits of RAS inhibitor use in patients with advanced CKD. Results of an observational study suggested that discontinuation of RAS inhibitors in that patient population may increase eGFR. Current guidelines do not offer specific recommendations on whether to stop or continue ACE inhibitors or ARBs for advanced CKD.

The researchers conducted the multicenter, randomized, open-label STOP-ACEi trial of patients with advanced and progressive CKD. The trial was designed to determine whether the discontinuation of RAS inhibitors would increase or stabilize eGFR. Results were reported in the New England Journal of Medicine [2022;387(22):2021-2032].

Patients with advanced and progressive CKD (eGFR <30 mL/min/1.73 m2) were randomly assigned to either discontinue or to continue therapy with RAS inhibitors. The primary outcome of interest was eGFR at 3 years as calculated according to the Modification of Diet in Renal Disease (MDRD) study updated in 2005; eGFR values that were obtained following initiation of RRT were excluded. Secondary outcomes were the development of end-stage kidney disease (ESKD); a composite of a decrease of >50% in eGFR or the initiation of RRT, including ESKD; hospitalization; blood pressure; exercise capacity; and quality of life. Prespecified subgroups were defined according to age, eGFR, type of diabetes, mean arterial pressure, and proteinuria.

Analyses were based on the intention-to-treat (ITT) principle and were adjusted for the minimization variables and baseline values (where available). The ITT population included all patients who had undergone randomization, regardless of what treatment (if any) they had received. The between-group difference in eGFR at 3 years was estimated using a repeated-measures, mixed-effects, linear regression model that included a term for the interaction of time with treatment group. The researchers repeated analyses for the primary outcome with the use of two other four-variable equations for the eGFR calculation: the Chronic Kidney Disease Epidemiology Collaboration 2009 (CKD-EPI 2009) equation and the MDRD186 equation.

A total of 17,290 patients were screened from July 11, 2014, to June 19, 2018, at the 39 participating centers in the United Kingdom. Of the 17,290 patients, 1210 were invited to participate in the trial. Of those, 411 at 37 centers underwent randomization to a trial group; 206 were assigned to the discontinuation group and 205 were assigned to the continuation group. Follow-up continued until June 19, 2021; median follow-up was 3 years.

Median age of the total cohort was 63 years, 68% (n=281) were male, and 15% (n=60) were non-White. At baseline, median eGFR was 18 mL/min/1.73 m2; 118 patients (29%) had eGFR <15 mL/min/1.73 m2. Median protein-to-creatinine ratio was 1018 and median hemoglobin level was 11.6 g/dL. Thirty-seven percent (n=153) had been diagnosed with diabetes (either type 1 or type 2), 21% (n=87) with diabetic nephropathy, 17% (n=68) with hypertensive or renovascular nephropathy, 20% (n=81) with genetic diseases, and 18% (n=76) with glomerulonephritis.

Clinically overt cardiovascualr disease was not common. Fifty-eight percent of patients were taking three or more antihypertensive medications, and 65% (n=268) were receiving a statin.

At 3 years, the least-squares mean eGFR was 12 mL/min/1.73 m2 in the discontinuation group and 13.3 mL/min/1.73 m2 in the continuation group (difference, –0.7; 95% CI, –2.5 to 1.0; P=.42), with a negative value favoring the outcome in the continuation group. There was no heterogeneity in outcome according to the prespecified subgroups.

At 3 years, 128 of 206 patients (62%) in the discontinuation group had reached ESKD or RRT, as had 115 of 205 patients (56%) in the continuation group (adjusted hazard ratio [HR], 1.28; 95% CI, 0.99-1.65). The number of patients who initiated RRT (including those with ESRD) or had a decrease of >50% in eGFR was 140 of 206 (68%) in the discontinuation group and 127 of 202 (63%) in the continuation group (adjusted relative risk, 1.07; 95% CI, 0.94-1.22).

The numbers of hospitalizations for any reason were similar in the discontinuation group and the continuation group (414 and 413, respectively), as were the numbers of cardiovascular events (108 and 88, respectively). A total of 20 patients in the discontinuation group and 22 patients in the continuation group died (HR, 0.85; 95% CI, 0.46-1.57).

In the 15 months following randomization, systolic and diastolic blood-pressure values were higher in the discontinuation group compared with the continuation group. After the first 15 months, values were similar in the two groups. The number of antihypertensive medications prescribed were also similar in the two groups.

At 3 years, the least-squares mean distance covered during a 6-minute walk test was 394 meters in the discontinuation group and 412 meters in the continuation group. The two groups were similar in various measurements of quality of life. There was little difference between the two groups in the urinary protein to creatinine ratio at 3 years. Mean hemoglobin was also similar in the two groups.

Limitations cited by the authors included poor representation of patients with non-White ethnic backgrounds, limiting the generalizability of the findings; the open-label design that may have affected clinical care and subjective end points, including quality of life and exercise capacity; and the possibility that the findings may not generalize to patients with higher levels of proteinuria.

In conclusion, the researchers said, “In this trial, the discontinuation of RAS inhibitors in patients with advanced and progressive chronic kidney disease did not lead to a clinically relevant change in the eGFR or a between-group difference in the long-term rate of decline in eGFR.”

Takeaway Points

  1. Researchers in the United Kingdom reported results of a study in patients with advanced and progressive chronic kidney disease to assess whether the discontinuation of renin-angiotensin system (RAS) inhibitors would increase or stabilize estimated glomerular filtration rate (eGFR).
  2. Patients were randomized to discontinue or continue therapy with RAS inhibitors, There was no association between the discontinuation of RAS inhibitors and a significant between-group difference in the long-term rate of decrease in eGFR.
  3. The two group were similar regarding adverse events, including cardiovascular events and death.