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

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; ATHOS-3 Investigators

doi:10.1186/s13054-024-04910-6

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

Crit Care. 2024 Apr 18;28(1):130. doi: 10.1186/s13054-024-04910-6.

Authors

Daniel E Leisman¹, Damian R Handisides², Laurence W Busse^{3

4}, Mark C Chappell⁵, Lakhmir S Chawla⁶, Michael R Filbin^{7

8

9}, Marcia B Goldberg^{9

10

11}, Kealy R Ham¹², Ashish K Khanna^{13

14

15}, Marlies Ostermann¹⁶, Michael T McCurdy^{17

18}, Christopher D Adams², Tony N Hodges², Rinaldo Bellomo^{19

20

21

22

23

24}; ATHOS-3 Investigators

Affiliations

¹ Department of Medicine, Massachusetts General Hospital, 55 Fruit St., GRB 7-730, Boston, MA, 02114, USA. dleisman@mgh.harvard.edu.
² Innoviva Specialty Therapeutics, Inc - an Affiliate of La Jolla Pharmaceutical Company, Waltham, MA, USA.
³ Department of Medicine, Emory University, Atlanta, GA, USA.
⁴ Emory Critical Care Center, Emory Healthcare, Atlanta, GA, USA.
⁵ Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
⁶ Department of Medicine, Veterans Affairs Medical Center, San Diego, CA, USA.
⁷ Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁸ Department of Emergency Medicine, Harvard Medical School, Boston, MA, USA.
⁹ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
¹⁰ Division of Infectious Diseases, Department of Medicine, Center for Bacterial Pathogenesis, Massachusetts General Hospital, Boston, MA, USA.
¹¹ Department of Microbiology, Harvard Medical School, Boston, MA, USA.
¹² Department of Critical Care, Mayo Clinic, Phoenix, AZ, USA.
¹³ Section on Critical Care Medicine, Department of Anesthesiology, Wake Forest University School of Medicine, Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, NC, USA.
¹⁴ Perioperative Outcomes and Informatics Collaborative (POIC), Winston-Salem, NC, USA.
¹⁵ Outcomes Research Consortium, Cleveland, OH, USA.
¹⁶ Department of Critical Care, King's College London, Guy's & St Thomas' Hospital, London, UK.
¹⁷ Division of Pulmonary & Critical Care Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
¹⁸ Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
¹⁹ Australian and New Zealand Intensive Care Research Centre (ANZIC-RC), School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.
²⁰ Department of Critical Care, Melbourne Medical School, University of Melbourne, Austin Hospital, Melbourne, Australia.
²¹ Data Analytics Research and Evaluation (DARE) Centre, Austin Hospital, Melbourne, Australia.
²² Department of Intensive Care Medicine, Austin Hospital, Melbourne, Australia.
²³ The Australian and New Zealand Intensive Care Society (ANZICS) Centre for Outcome and Resource Evaluation (CORE), Melbourne, Australia.
²⁴ Intensive Care Unit, Royal Melbourne Hospital, Melbourne, VIC, Australia.

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: NCT02338843 (Registered January 14th 2015).

Keywords: Angiotensin II; Norepinephrine; Renin–angiotensin system; Septic; Shock.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Angiotensin II / therapeutic use
Angiotensin Receptor Antagonists / adverse effects
Angiotensin-Converting Enzyme Inhibitors* / adverse effects
Humans
Norepinephrine / therapeutic use
Renin
Shock* / drug therapy

Substances

Angiotensin-Converting Enzyme Inhibitors
Angiotensin II
Renin
Angiotensin Receptor Antagonists
Norepinephrine

Associated data

ClinicalTrials.gov/NCT02338843