Do You Stop RAS Inhibitors in CKD Patients?

From the Chair

Renin–angiotensin system (RAS) inhibitors are a class of agents that include angiotensin-converting enzyme (ACE) inhibitors, such as lisinopril, or angiotensin-receptor blockers, such as losartan, which are recommended for slowing of kidney disease.

We are often asked whether RAS inhibition should be discontinued to stave off initiation of dialysis because stopping the RAS inhibitor might increase the estimated glomerular filtration rate (eGFR). The idea is the mirror opposite of what happens when beginning a patient on a RAS inhibitor, where a small drop in eGFR is usually observed. Current guidelines do not speak to this issue, although post hoc analyses of the REIN and RENAAL trials^1,2 suggested that discontinuation of RAS inhibitors might be beneficial. Until now, however, there had not been a randomized controlled trial to examine this question.

The STOP ACEi trial³, published very recently in the New England Journal of Medicine by Bhandari and colleagues from the UK, tested the hypothesis that discontinuation of RAS inhibitors in patients with advanced and progressive chronic kidney disease (CKD) would improve kidney function, quality of life, and/or exercise capacity. The trial was very well conducted.

Online publication in the journal coincided with a presentation at the American Society of Nephrology Kidney Week 2022. Surprisingly, the submission didn’t make it into the high-impact clinical trials session (the late breaker session), but it was presented as a poster at the meeting.

In a nutshell, the STOP ACEi trial was a multicenter, randomized, controlled, open-label study that enrolled 411 patients with advanced and progressive CKD (stage 4 or stage 5). Patients were required to demonstrate kidney progression (an eGFR decrease of >2 ml/min/1.73 m² per year during the previous 2 years) and have received treatment with a RAS inhibitor for >6 months. A total of 206 patients were randomized to the “discontinue RAS inhibitors” arm and 205 to the “continue RAS inhibitors” arm.

Baseline characteristics were balanced. Overall, about one-third of patients had a history of diabetes mellitus. The median follow-up was 3 years. About 10% of patients in each arm discontinued the randomized treatment. The primary outcome was eGFR at 3 years and secondary end points included the development of end-stage renal disease (ESRD), a composite of a decrease of more than 50% in the eGFR, or the initiation of renal replacement therapy. Other secondary end points included hospitalization, blood pressure, exercise capacity, and quality of life.

The main finding from the trial was that stopping RAS inhibitors did not slow kidney decline. The eGFR was similar between the two arms (P=.42). Secondary outcomes and analysis by subgroups also did not show any meaningful differences between the two arms of the study. Serious adverse events were similar between the two arms.

There was a tantalizing observation suggesting that there might be a benefit from continuing RAS inhibition. ESRD or the initiation of renal-replacement therapy occurred in 128 patients (62%) in the discontinuation group and in 115 patients (56%) in the continuation group (hazard ratio, 1.28; 95% CI, 0.99-1.65), just missing statistical significance. However, a word of caution: since the primary end point was null, and the result was a trend, this result needs to be confirmed in a larger trial.

The trial had several limitations that the authors acknowledged, including the open-label design that might have influenced reported outcomes or hospitalization and the under-representation of non-White patients and those with high levels of proteinuria (>2.6 g/g creatinine). As well, because this was a UK-based study and Black and Latino patients were not recruited, the results may not be generalizable to the US population.

The bottom line from a practice perspective is that you should not stop RAS inhibition unless the patient becomes intolerant or refractory hyperkalemia develops. Indeed, I keep patients on RAS inhibition even after they begin dialysis with the aim of preserving residual renal function.

References

1. Ruggenenti P, Perna A, Remuzzi G. ACE inhibitors to prevent end-stage renal disease: when to start and why possibly never to stop: a post hoc analysis of the REIN trial results. Ramipril Efficacy in Nephropathy. J Am Soc Nephrol. 2001;12:2832-2837.
2. Remuzzi G, Ruggenenti P, Perna A, et al. RENAAL Study Group. Continuum of renoprotection with losartan at all stages of type 2 diabetic nephropathy: a post hoc analysis of the RENAAL trial results. J Am Soc Nephrol. 2004;15:3117-3125.
3. Bhandari S, Mehta S, Khwaja A, et al. STOP ACEi Trial Investigators. Renin–angiotensin system inhibition in advanced chronic kidney disease. N Engl J Med. 2022. doi:10.1056/NEJMoa2210639. PMID:36326117.