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Original Investigation
March 9, 2020

Association Between Renin-Angiotensin System Blockade Discontinuation and All-Cause Mortality Among Persons With Low Estimated Glomerular Filtration Rate

Author Affiliations
  • 1Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
  • 2Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland
  • 3Division of Nephrology, Department of Internal Medicine, Johns Hopkins University, Baltimore, Maryland
  • 4Division of Nephrology, Department of Medicine, Tufts Medical Center, Boston, Massachusetts
  • 5Division of Nephrology, Geisinger Health System, Danville, Pennsylvania
JAMA Intern Med. 2020;180(5):718-726. doi:10.1001/jamainternmed.2020.0193
Key Points

Question  Is there an association between discontinuing renin-angiotensin system blockade after estimated glomerular filtration rate (eGFR) decreases to less than 30 mL/min/1.73 m2 and the risk of all-cause mortality, major adverse cardiovascular events, and end-stage kidney disease in the subsequent 5 years?

Findings  In this cohort study of 3909 individuals who had initiated angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker therapy and experienced an eGFR decrease to below 30 mL/min/1.73 m2 during therapy, 35.1% of those who discontinued therapy within 6 months after the eGFR decrease died during the subsequent 5 years compared with 29.4% of those who did not discontinue therapy.

Meaning  These findings suggest that continued angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker use is associated with cardiovascular health benefits in individuals with an eGFR below 30 mL/min/1.73 m2, without increased risk of progression to end-stage kidney disease.

Abstract

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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    2 Comments for this article
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    How many patients re-started therapy? Were discontinued-group taken BP control by other class drugs such as Ca channel blockers
    Masao Tomita, MD, PhD. | National Hospital Organization Kumamoto Medical Center

    I appreciate the contribution of this study for CKD patients in G4 and G5. In order to understand the study better, I have two questions.

    First, with regard to the performance of  an intention-to-treat analysis that provided an effect estimate based on the initial treatment decision: many patients who discontinued therapy then re-started therapy within the follow-up period. 

    About how many patients re-started ACE-I and/or ARB? If the majority of patients re-started the therapy, the study may indicate that CKD G4 patients who have to discontinue ACE and/or ARB for some reason would have worse outcomes,  with or
    without ACE-I and/or ARB.

    Second, were the patients who discontinued ACE-I and/or ARB taking blood pressure medications in other classes, such as calcium channel blockers? 

    CONFLICT OF INTEREST: None Reported
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    RE: Association between renin-angiotensin system blockade discontinuation and all-cause mortality among persons with low eGFR
    Tomoyuki Kawada, MD | Nippon Medical School
    Qiao et al. conducted a retrospective cohort study to investigate the association of angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II receptor blocker (ARB) therapy discontinuation after estimated glomerular filtration rate (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). Hazard ratio (HR) (95% confidence intervals [CIs]) of ACE-I or ARB therapy discontinuation for mortality, MACE, and ESKD were 1.39 (1.20-1.60), 1.37 (1.20-1.56), and 1.19 (0.86-1.65), respectively. The authors concluded that continuing ACE-I or ARB therapy in patients with declining kidney function has cardiovascular benefit without excessive harm of ESKD. I have a query about their study.

    The same authors presented the patterns of an ACE-I/ARB discontinuation in the setting of chronic kidney disease (CKD) progression. They selected ACE-I/ARB users with a baseline eGFR ≥15 mL/min/1.73 m2 and without ESRD. Discontinuation of ACE-I/ARB was common in patients with lower eGFR. In addition, hyperkalemia, hypotension, low bicarbonate level, and AKI-related hospitalization were significantly associated with a higher risk of discontinuation. Furthermore, thiazide diuretic use was associated with lower risk, and loop diuretic use was associated with higher risk of discontinuation. Acute biological risk prohibits ACE-I/ARB continuation, although long-term mortality and MACE risk increase subsequently. I suppose that clinical decision-making might be indispensable in these real-world cases. As there is a bias in a retrospective cohort study, a prospective study is recommended for conducting unbiased risk estimation.


    References
    1. Qiao Y, Shin JI, Chen TK, et al. Association between renin-angiotensin system blockade discontinuation and all-cause mortality among persons with low estimated glomerular filtration rate. JAMA Intern Med. 2020;180(5):718-726. doi:10.1001/jamainternmed.2020.0193
    2. Qiao Y, Shin JI, Sang Y, et al. Discontinuation of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in chronic kidney disease. Mayo Clin Proc. 2019;94(11):2220-2229. doi:10.1016/j.mayocp.2019.05.031
    CONFLICT OF INTEREST: None Reported
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