Association between renin-angiotensin system blockade discontinuation and all-cause mortality among persons with low estimated glomerular filtration rate
Open accessAbstract
Importance: It is uncertain whether and when angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) treatment should be discontinued in individuals with low estimated glomerular filtration rate (eGFR). Objective: To investigate the association of ACE-I or ARB therapy discontinuation after eGFR decreases to below 30 mL/min/1.73 m2 with the risk of mortality, major adverse cardiovascular events (MACE), and end-stage kidney disease (ESKD). Design, Setting, and Participants: This retrospective, propensity score-matched cohort study included 3909 patients from an integrated health care system that served rural areas of central and northeastern Pennsylvania. Patients who initiated ACE-I or ARB therapy from January 1, 2004, to December 31, 2018, and had an eGFR decrease to below 30 mL/min/1.73 m2 during therapy were enrolled, with follow-up until January 25, 2019. Exposures: Individuals were classified based on whether they discontinued ACE-I or ARB therapy within 6 months after an eGFR decrease to below 30 mL/min/1.73 m2. Main Outcomes and Measures: The association between ACE-I or ARB therapy discontinuation and mortality during the subsequent 5 years was assessed using multivariable Cox proportional hazards regression models, adjusting for patient characteristics at the time of the eGFR decrease in a propensity score-matched sample. Secondary outcomes included MACE and ESKD. Results: Of the 3909 individuals receiving ACE-I or ARB treatment who experienced an eGFR decrease to below 30 mL/min/1.73 m2 (2406 [61.6%] female; mean [SD] age, 73.7 [12.6] years), 1235 discontinued ACE-I or ARB therapy within 6 months after the eGFR decrease and 2674 did not discontinue therapy. A total of 434 patients (35.1%) who discontinued ACE-I or ARB therapy and 786 (29.4%) who did not discontinue therapy died during a median follow-up of 2.9 years (interquartile range, 1.3-5.0 years). In the propensity score-matched sample of 2410 individuals, ACE-I or ARB therapy discontinuation was associated with a higher risk of mortality (hazard ratio [HR], 1.39; 95% CI, 1.20-1.60]) and MACE (HR, 1.37; 95% CI, 1.20-1.56), but no statistically significant difference in the risk of ESKD was found (HR, 1.19; 95% CI, 0.86-1.65). Conclusions and Relevance: The findings suggest that continuing ACE-I or ARB therapy in patients with declining kidney function may be associated with cardiovascular benefit without excessive harm of ESKD.
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Among people with type 1 or 2 diabetes with established CKD (eGFR <60 mL/min/1.73m2 and UACR >=300 mg/g creatinine), ACE inhibitor or ARB therapy reduces the risk of progression to ESKD.
“Antihypertensive therapy reduces the risk of albuminuria (67)(68)(69)(70), and among people with type 1 or 2 diabetes with established CKD (eGFR <60 mL/min/1.73m 2 and UACR $300 mg/g creatinine), ACE inhibitor or ARB therapy reduces the risk of progression to ESKD (71)(72)(73)(74)(75)(76)(77)(78)(79)(80).”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [80]
The Discussion reports a meta-analysis associating ACE inhibitor or ARB use with reduced kidney failure risk in patients with CKD, and the paper's subgroup analysis estimates a higher ESKD risk after discontinuation among participants with diabetes. However, it does not establish the claimed reduction specifically for people with type 1 or 2 diabetes who also meet both stated eGFR and UACR thresholds. In the overall study population, the Abstract reports no statistically significant difference in ESKD risk between those who continued and discontinued therapy. Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThere are now studies demonstrating outcome benefits on both mortality and slowed CKD progression in people with diabetes who have an eGFR <30 mL/min/1.73m2.
“Moreover, there are now studies demonstrating outcome benefits on both mortality and slowed CKD progression in people with diabetes who have an eGFR <30 mL/min/1.73m 2 (80).”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [80]
The Results report that, among people whose eGFR fell below 30 mL/min/1.73 m², discontinuing ACE-I or ARB therapy was associated with higher mortality; diabetes did not modify that association. A subgroup analysis found a higher estimated risk of end-stage kidney disease after discontinuation among participants with diabetes, but the Conclusions report no significant overall difference in that outcome. This observational evidence suggests possible benefits of continuing therapy, rather than demonstrating that it slows CKD progression. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThere are now studies demonstrating outcome benefits on both mortality and slowed CKD progression in people with diabetes who have an eGFR <30 mL/min/1.73m2.
“Moreover, there are now studies demonstrating outcome benefits on both mortality and slowed CKD progression in people with diabetes who have an eGFR <30 mL/ min/1.73m 2 (81).”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [81]
The Results (page not provided) associate continued ACE-I or ARB use after eGFR falls below 30 with lower mortality; they report no mortality effect modification by diabetes and a higher estimated ESKD risk after discontinuation among participants with diabetes. But this observational study does not demonstrate that treatment slows CKD progression: its overall ESKD association was not significant, and ESKD risk is not a direct measure of the rate of progression. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn individuals receiving ACE inhibitor or ARB therapy, continuation of those medications as kidney function declines to eGFR <30 mL/min/1.73 m2 may provide cardiovascular benefit without significantly increasing the risk of end-stage kidney disease.
“In individuals receiving ACE inhibitor or ARB therapy, continuation of those medications as kidney function declines to estimated glomerular filtration rate (eGFR) <30 mL/min/ 1.73 m 2 may provide cardiovascular benefit without significantly increasing the risk of end-stage kidney disease (74).”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [74]
In individuals receiving ACE inhibitor or ARB therapy, continuation of those medications as kidney function declines to eGFR <30 mL/min/1.73 m2 may provide cardiovascular benefit without significantly increasing the risk of kidney failure.
“In individuals receiving ACE inhibitor or ARB therapy, continuation of those medications as kidney function declines to eGFR <30 mL/min/1.73 m2 may provide cardiovascular benefit without significantly increasing the risk of kidney failure (68).”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [68]
Continuing ACE inhibitor or ARB therapy as kidney function declines to eGFR below 30 mL/min/1.73 m2 may provide cardiovascular benefit without significantly increasing end-stage kidney disease risk.
“In patients receiving ACE inhibitor or ARB therapy, continuation of those medications as kidney function declines to estimated glomerular fi ltration rate (eGFR) < 30 mL/min/1.73 m 2 may provide cardiovascular bene fi t without signi fi cantly increasing the risk of end-stage kidney disease (67).”
From 10. Cardiovascular Disease and Risk Management: <i>Standards of Care in Diabetes—2023</i> (2023) · cites this paper as [67]
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References 34 · Cited by 199
Research works printed but not linked: 1
- [5]5. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Rev Esp Cardiol (Engl Ed). 2016;69(12):1167. doi:10.1016/j.rec.2016. 11.005 · DOI
- Authors
- Qiao, Y., Shin, J.-I., Chen, T. K., Inker, L. A., Coresh, J., Alexander, G. C., Jackson, J. W., Chang, A. R., & Grams, M. E.
- Affiliations
- Johns Hopkins University (US)
- Tufts Medical Center (US)
- Geisinger Medical Center (US)
- Corresponding author
- Grams, Morgan E.
- ORCID
- Venue
- JAMA Internal Medicine
- Publisher
- American Medical Association (AMA)
- Published
- 2020-05-01
- Volume
- 180
- Issue
- 5
- Pages
- 718
- ISSN
- 2168-6106 (ISSN-L)
- PMC
- PMC7063544
- OpenAlex
- W3010053023
- Cited by
- 199
- References
- 34
- Citations by year
- 2026: 18 · 2025: 31 · 2024: 39 · 2023: 38 · 2022: 25 · 2021: 28 · 2020: 19 · 2012: 1
- FWCI
- 17.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Internal Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (K01DK121825, R01DK100446, R01DK115534)
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Keywords
- renin-angiotensin system blockade, ACE inhibitors, angiotensin receptor blockers, estimated glomerular filtration rate, chronic kidney disease, all-cause mortality, major adverse cardiovascular events, end-stage renal disease, rural health care, renal function decline, cardiovascular risk stratification
- MeSH terms
- Aged, Aged, 80 and over, Angiotensin-Converting Enzyme Inhibitors, Coronary Artery Disease, Female, Glomerular Filtration Rate, Heart Failure, Humans, Hypertension, Kidney Failure, Chronic, Male, Middle Aged, Renin-Angiotensin System, Retrospective Studies, Risk Factors, Propensity Score, Angiotensin Receptor Antagonists
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