ACE/ARB Therapy Should Continue in Worsening Kidney Disease

Marlene Busko

March 11, 2020

Patients receiving an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) who had mild chronic kidney disease (CKD) that became advanced had better 5-year survival if they did not stop the medication in a large, real-world study.

Discontinuing therapy with an ACE inhibitor or ARB within 6 months of developing advanced CKD was linked with a 39% increased risk of death and a 37% increased risk of a major adverse cardiovascular event (MACE; defined as death, myocardial infarction, percutaneous coronary intervention, or coronary artery bypass graft) during follow-up.

The study shows that "continuing these medications may actually provide cardiovascular and survival benefit" for people with advanced CKD, lead author Yao Qiao, MSc, MPH, from the Johns Hopkins University Bloomberg School of Public Health in Baltimore, Maryland, told Medscape Medical News.

The study, published online March 9 in JAMA Internal Medicine, sheds new light on a common clinical dilemma, Richard W. Grant, MD, MPH, Kaiser Permanente Northern California, in Oakland, and an associate editor for the journal, told Medscape Medical News.

"It's kind of like this two-edged sword," he explained. "We know that ACE inhibitors and ARBs are very useful to help prevent cardiovascular disease and renal disease progression," but they also reduce blood flow to the kidneys.

As estimated glomerular filtration rate (eGFR), a measure of how well the kidneys are working, worsens, "we need to make sure that there is enough blood flow [to the kidneys] and that's when doctors would need to decide whether to stop the ACE inhibitor or the ARB," he continued.

"As you go into the further and further stages of kidney disease, this decision [of whether to discontinue therapy] needs to be made, and it's not clear what to do. It would be terrible if we kept patients on ACE inhibitors or ARBs as their kidney function got worse, to the point where we made them go into kidney failure," he said.

This latest study shows that among patients who developed advanced CKD, those who stayed on ACE inhibitors or ARBs did no worse and, in some ways, did better.

"So that's a pretty good signal that we're not hurting people by continuing them on their ACE inhibitors or ARBs," Grant asserted.

And although this is not randomized control trial–level data, "it is reassuring," he stressed.

A Clinical Quandary

Renin-angiotensin system (RAS) blockade with an ACE inhibitor or ARB is indicated for hypertension, albuminuric CKD, heart failure with reduced ejection fraction, and coronary artery disease, Qiao and colleagues note.

In 2012, for example, an estimated 12% of US adults were treated with an ACE inhibitor and 5.8% were treated with an ARB, says Grant, along with Colette DeJong, MD, from the University of California, San Francisco, in an accompanying editorial.

Although these agents can potentially cause hyperkalemia and acute kidney injury, they also still protect the kidneys in advanced CKD.

So there is a "clinical quandary of what to do when patients taking these drugs show progression of kidney disease," the editorialists write.

To investigate this, Qiao and colleagues identified 3909 patients who were part of the Geisinger Health System in rural Pennsylvania, had mild CKD, and were started on an ACE inhibitor or ARB and subsequently had an eGFR <30 mL/min/1.73m2, indicating advanced (stage 4) CKD.

The patients were a mean age of 74 years; 62% were women and 49% had diabetes.

A total of 1235 patients discontinued their ACE inhibitor or ARB therapy within 6 months of developing advanced CKD; the remaining patients did not.

Researchers matched 1205 individuals who discontinued ACE inhibitor or ARB therapy with 1205 individuals who did not.

During a median follow-up of 2.9 years, 434 patients (35.1%) who discontinued ACE inhibitor or ARB therapy and 786 (29.4%) who did not died within 5 years.

In the propensity score–matched sample, ACE inhibitor or ARB therapy discontinuation was associated with a statistically higher risk of death (hazard ratio [HR], 1.39) and MACE (HR, 1.37).

In addition, 7% of patients who discontinued ACE inhibitor or ARB therapy and 6.6% who did not discontinue therapy developed end-stage kidney disease within 5 years. There was no significant difference between these two groups in the propensity score–matched sample analysis.

Similarly, the risk of acute kidney injury (AKI) was not significantly different between the two groups. 

However, during a median follow-up of 2.3 years, 15.6% of patients who discontinued ACE inhibitor or ARB therapy versus 22% of patients who did not experience hyperkalemia, which was a significant difference (HR, 0.65).  

The finding that therapy discontinuation was associated with a lower risk of hyperkalemia is consistent with existing evidence, say Qiao and colleagues. However, "this risk did not appear to outweigh the potential cardiovascular and survival benefits of continuing ACE inhibitor or ARB therapy," they stress.

Useful Data in Advance of STOP-ACEi Trial

Grant acknowledged to Medscape Medical News that "There are drawbacks to observational data because we don't know why [these medications] were continued or discontinued, and we don't have as much detail as to what's happening at the time."

But nevertheless, the study provides "useful data" in advance of the multicenter randomized controlled trial of ACE inhibitor/ARB withdrawal in advanced renal disease (STOP-ACEi), funded by the UK National Institute for Health Research, which completed enrollment at 20 UK centers in 2018. Published results are expected at the end of December 2022.

The trial enrolled adults who were receiving an ACE inhibitor or ARB and whose renal function had deteriorated to stage 4 CKD. It will randomize 410 patients to discontinue or not discontinue treatment and follow them for 3 years.    

However, in the meantime, Grant said, "by looking at usual care in selected patients," such as those in the current large, real-world, observational study, clinicians "can get some insight into what's the right thing to do."

"And even when randomized control trial studies are available," the editorialists write, "results must be interpreted in the context of the patient sitting in your office."

"Qiao et al present strong evidence that continuing ACE inhibitor/ARB therapy as tolerated in typical patients with chronic kidney disease with declining kidney function does not lead to harm and is associated with reduced mortality," they conclude.

The study was supported by grants from the National Institutes of Health/ National Institute of Diabetes and Digestive and Kidney Diseases. Qiao has reported no relevant financial relationships. Disclosures for the other authors are listed in the article.

JAMA Intern Med. Published online March 9, 2020. Full text, Editorial

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