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Open Access 01-12-2024 | Shock | Research

ACE inhibitors and angiotensin receptor blockers differentially alter the response to angiotensin II treatment in vasodilatory shock

Authors: Daniel E. Leisman, Damian R. Handisides, Laurence W. Busse, Mark C. Chappell, Lakhmir S. Chawla, Michael R. Filbin, Marcia B. Goldberg, Kealy R. Ham, Ashish K. Khanna, Marlies Ostermann, Michael T. McCurdy, Christopher D. Adams, Tony N. Hodges, Rinaldo Bellomo, The ATHOS-3 Investigators

Published in: Critical Care | Issue 1/2024

Abstract

Background

Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARB) medications are widely prescribed. We sought to assess how pre-admission use of these medications might impact the response to angiotensin-II treatment during vasodilatory shock.

Methods

In a post-hoc subgroup analysis of the randomized, placebo-controlled, Angiotensin Therapy for High Output Shock (ATHOS-3) trial, we compared patients with chronic angiotensin-converting enzyme inhibitor (ACEi) use, and patients with angiotensin receptor blocker (ARB) use, to patients without exposure to either ACEi or ARB. The primary outcome was mean arterial pressure after 1-h of treatment. Additional clinical outcomes included mean arterial pressure and norepinephrine equivalent dose requirements over time, and study-drug dose over time. Biological outcomes included baseline RAS biomarkers (renin, angiotensin-I, angiotensin-II, and angiotensin-I/angiotensin-II ratio), and the change in renin from 0 to 3 h.

Results

We included n = 321 patients, of whom, 270 were ACEi and ARB-unexposed, 29 were ACEi-exposed and 22 ARB-exposed. In ACEi/ARB-unexposed patients, angiotensin-treated patients, compared to placebo, had higher hour-1 mean arterial pressure (9.1 mmHg [95% CI 7.6–10.1], p < 0.0001), lower norepinephrine equivalent dose over 48-h (p = 0.0037), and lower study-drug dose over 48-h (p < 0.0001). ACEi-exposed patients treated with angiotensin-II showed similarly higher hour-1 mean arterial pressure compared to ACEi/ARB-unexposed (difference in treatment-effect: − 2.2 mmHg [95% CI − 7.0–2.6], p_interaction = 0.38), but a greater reduction in norepinephrine equivalent dose (p_interaction = 0.0031) and study-drug dose (p_interaction < 0.0001) over 48-h. In contrast, ARB-exposed patients showed an attenuated effect of angiotensin-II on hour-1 mean arterial pressure versus ACEi/ARB-unexposed (difference in treatment-effect: − 6.0 mmHg [95% CI − 11.5 to − 0.6], p_interaction = 0.0299), norepinephrine equivalent dose (p_interaction < 0.0001), and study-drug dose (p_interaction = 0.0008). Baseline renin levels and angiotensin-I/angiotensin-II ratios were highest in ACEi-exposed patients. Finally, angiotensin-II treatment reduced hour-3 renin in ACEi/ARB-unexposed and ACEi-exposed patients but not in ARB-exposed patients.

Conclusions

In vasodilatory shock patients, the cardiovascular and biological RAS response to angiotensin-II differed based upon prior exposure to ACEi and ARB medications. ACEi-exposure was associated with increased angiotensin II responsiveness, whereas ARB-exposure was associated with decreased responsiveness. These findings have clinical implications for patient selection and dosage of angiotensin II in vasodilatory shock.

Trial Registration ClinicalTrials.Gov Identifier: NCT 02338843 (Registered January 14th 2015).

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Title: ACE inhibitors and angiotensin receptor blockers differentially alter the response to angiotensin II treatment in vasodilatory shock
Authors: Daniel E. Leisman
Damian R. Handisides
Laurence W. Busse
Mark C. Chappell
Lakhmir S. Chawla
Michael R. Filbin
Marcia B. Goldberg
Kealy R. Ham
Ashish K. Khanna
Marlies Ostermann
Michael T. McCurdy
Christopher D. Adams
Tony N. Hodges
Rinaldo Bellomo
The ATHOS-3 Investigators
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Shock
Shock
Published in: Critical Care / Issue 1/2024
Electronic ISSN: 1364-8535
DOI: https://doi.org/10.1186/s13054-024-04910-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

ACE inhibitors and angiotensin receptor blockers differentially alter the response to angiotensin II treatment in vasodilatory shock

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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