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Editor's Note
March 9, 2020

Continuation of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in the Face of Kidney Disease Progression—Safe and Possibly Life Saving

Author Affiliations
  • 1Department of Medicine, University of California, San Francisco
  • 2Division of Research, Kaiser Permanente Northern California, Oakland
  • 3Associate Editor, JAMA Internal Medicine
JAMA Intern Med. Published online March 9, 2020. doi:10.1001/jamainternmed.2020.0300

According to the National Health and Nutrition Examination Survey, from 2011 to 2012, an estimated 12% of adults in the US used an angiotensin-converting enzyme inhibitor (ACE-I) and 5.8% used an angiotensin receptor blocker (ARB).1 In this issue of JAMA Internal Medicine, Qiao et al2 help inform the clinical quandary of what to do when patients taking these drugs show progression of kidney disease. They present results of a retrospective cohort study investigating the association of ACE-I/ARB discontinuation after kidney disease progression with subsequent morbidity and mortality. Qiao et al2 identified patients prescribed ACE-I/ARBs whose estimated glomerular filtration rate was less than 30 mL/min/1.73 m2 and compared clinical outcomes of 1233 patients who had ACE-I/ARB discontinued with a propensity score–matched sample of 2673 patients who did not. In a 5-year follow-up, ACE-I/ARB discontinuation was associated with an increased risk of both mortality (hazard ratio, 1.39; 95% CI, 1.20-1.60) and major adverse cardiovascular events (hazard ratio, 1.37; 95% CI, 1.20-1.56).

The study by Qiao et al2 provides useful data in advance of the Multicentre Randomized Controlled Trial of Angiotensin-Converting Enzyme Inhibitor/Angiotensin Receptor Blocker Withdrawal in Advanced Renal Disease (STOP-ACEi) trial,3 a 3-year, multicenter, open-label randomized clinical trial (RCT), which concluded recruitment of 410 participants in June 2018. Although RCTs are a criterion standard in clinical research, large cohort studies, like the analysis by Qiao et al,2 can complement RCTs by examining the clinical question in more diverse clinical settings. Compared with the STOP-ACEi trial,3 Qiao et al2 observed nearly 10-fold more patients over a longer study period, allowing for greater external validity (albeit in a predominantly white sample) and a primary end point of clinical events rather than the surrogate of change in estimated glomerular filtration rate.

As with all observational studies, the findings by Qiao et al2 may be subject to unmeasured confounding. Because the clinical rationale for ACE-I/ARB discontinuation, such as hyperkalemia or overall clinical trajectory, was not captured in the data source, there may have been unmeasured differences in health status between the groups that could partially explain the increased mortality among patients whose ACE-I/ARB therapy was discontinued. Although Qiao et al2 used propensity score matching and a negative control analysis using bleeding risk, the results of the STOP-ACEi trial will provide RCT data to better establish cause and effect.

While we await results of RCTs, clinical decisions must still be made. And even when RCT studies are available, results must be interpreted in the context of the patient sitting in your office. Qiao et al2 present strong evidence that continuing ACE-I/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.

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Article Information

Published Online: March 9, 2020. doi:10.1001/jamainternmed.2020.0300

Corresponding Author: Richard W. Grant, MD, MPH, Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA 94612 (richard.w.grant@kp.org).

Conflict of Interest Disclosures: None reported.

References
1.
Kantor  ED, Rehm  CD, Haas  JS, Chan  AT, Giovannucci  EL.  Trends in prescription drug use among adults in the United States from 1999-2012.  JAMA. 2015;314(17):1818-1831. doi:10.1001/jama.2015.13766PubMedGoogle ScholarCrossref
2.
Qiao  Y, Shin  J-I, Chen  TK,  et al.  Association between renin-angiotensin system blockade discontinuation and all-cause mortality among persons with low estimated glomerular filtration rate  [published online March 9, 2020].  JAMA Intern Med. doi:10.1001/jamainternmed.2020.0193Google Scholar
3.
Bhandari  S, Ives  N, Brettell  EA,  et al.  Multicentre Randomized Controlled Trial of Angiotensin-Converting Enzyme Inhibitor/Angiotensin Receptor Blocker Withdrawal in Advanced Renal Disease: the STOP-ACEi trial.  Nephrol Dial Transplant. 2016;31(2):255-261. doi:10.1093/ndt/gfv346PubMedGoogle Scholar
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