Randomized Controlled Trial

. 2024 Apr 18;28(1):130.

doi: 10.1186/s13054-024-04910-6.

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

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.

PMID: 38637829
PMCID: PMC11027368
DOI: 10.1186/s13054-024-04910-6

Randomized Controlled Trial

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

Daniel E Leisman et al. Crit Care. 2024.

. 2024 Apr 18;28(1):130.

doi: 10.1186/s13054-024-04910-6.

Authors

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.

PMID: 38637829
PMCID: PMC11027368
DOI: 10.1186/s13054-024-04910-6

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.

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Conflict of interest statement

DEL, LWB, MCC, MRF, MBG, KRH, AKK, MO, MTC, and RB declare no competing interests. DRH, CDA, and TNH are employees of Innoviva Specialty Therapeutics, of which La Jolla Pharmaceutical Company (LJPC) is a subsidiary. LSC declares that he was formerly an employee of LJPC.

Figures

**Fig. 1**
Schematic Diagram of the Classical RAS Axis and the Mechanism of ACEi and ARB medications. Renin catalyzes the conversion of angiotensinogen to angiotensin-I, which in turn is converted to angiotensin-II by ACE. Angiotensin-II primarily exerts its cardiovascular effects by stimulating the AT1R. ACEi medications act by inhibiting the conversion of the angiotensin-I to angiotensin-II. ARB medications act by directly antagonizing AT1R. *Ang* angiotensin, *ACE* angiotensin-converting enzyme, *ACEi* ACE-inhibitor, *ARB* angiotensin receptor blocker, *AT1R* angiotensin-II type-1 receptor, *RAS* renin-angiotensin system

**Fig. 2**
Early Cardiovascular Endpoints for Angiotensin-II versus Placebo Treatment According to ACEi and ARB Exposure Status. A MAP from baseline to hour 3 in Angiotensin-II (blue) versus placebo (red) treated patients, stratified by ACEi and ARB exposure status. Boxes indicate mean, error bars SEM. B Total NED from baseline to hour 48. Points indicate median, bars interquartile range. For No ACEi/ARB (left), p_Rx indicates the p-value for the overall effect of Angiotensin-II treatment versus placebo. For ACEi (middle) and ARB (right), p_int indicates the p-value for highest order interaction effect of ACEi or ARB with time and treatment, where p < 0.05 indicates an effect that significantly differs from the effect of treatment over time in the no ACEi/ARB group. C Study drug titration level over time. Boxes indicate mean, error bars SEM. P-values reflect longitudinal mixed effect model output as in B. *Ang-II* angiotensin-II, *ACEi* angiotensin converting enzyme inhibitor, *ARB* angiotensin receptor blocker, *MAP* mean arterial pressure, *NED* norepinephrine equivalent dose

**Fig. 3**
Biomolecular RAS profile according to ACEi and ARB exposure status. A–D Baseline renin, Ang-I, Ang-II, and Ang-I/Ang-II ratio according to ACEi and ARB medication exposure. Y-axes are on log2-scale. Bars indicate median, boxes IQR, whiskers data range. Dots represent individual patients. Δ indicates the difference in geometric mean between the indicated group, bracketed values the 95% CI. E Change in log-renin at hour 3 in angiotensin-II versus placebo treated patients, stratified by ACEi and ARB exposure status. Lower-level Δ and bracketed values reflect the difference and 95% CI from the unadjusted linear model, as above, for angiotensin-II versus placebo treatment within the ACEi/ARB exposure group. Upper-level Δ and bracketed values reflect the same, but for the interaction effect of treatment with ACEi/ARB medication group. The p_Rx shows the p-value for the effect of angiotensin-II versus placebo treatment in the no ACEi/ARB group. The p_int. reflects the p-value for the interaction effect of ACEi or ARB exposure with angiotensin-II treatment, where p_int. < 0.05 indicates a significantly different effect of treatment versus ACEi/ARB unexposed patients. *ang* angiotensin, *ACEi* angiotensin-converting enzyme inhibitor, *ARB* angiotensin receptor blocker

**Fig. 4**
Representative Plots of Interaction between ARB dose and Effect of Angiotensin-II on Main Study Outcomes. A–D Displays marginal effect sizes from multivariable models for key study outcomes in angiotensin-II and placebo arms at clinically relevant ARB doses in losartan equivalents. The models excluded the n = 29 ACEi-exposed patients (total sample n = 292). Losartan equivalents were modeled on a natural log scale to accommodate observed distributions. Unexposed patients were considered to have an ARB dose = 0 Log(mg). To facilitate interpretation, the estimates were plotted for the corresponding untransformed values at clinically relevant ARB doses along the X-axes. Results are plotted at representative time points for MAP (hr1), NED (hr6), study drug dose (hr3), and change in renin (hr3). Circles/squares show point estimates for placebo/angiotensin-II arms, respectively. Error bars 95% CIs. Key effect estimates from the multivariable models are displayed on the graph as follows: Ang-II = the treatment effect (i.e., in ARB-unexposed patients), Log(mg) = the main-effect of losartan equivalents (i.e., the effect in the placebo group), and Interaction = the interaction-effect of losartan equivalents with treatment (i.e., change in treatment effect per log(mg) increase in ARB dose). Brackets show the 95% confidence intervals for the effects. Full model output, including main and interaction effect sizes, and their confidence intervals can be found in Additional file 1: Tables S4–S8. *Ang-II* angiotensin-II, *ACEi* angiotensin converting enzyme inhibitor, *ARB* angiotensin receptor blocker, *MAP* mean arterial pressure, *NED* norepinephrine equivalent dose

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

Affiliations

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

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Abstract

Conflict of interest statement

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