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Observational Study
. 2022 Sep 1;50(9):1306-1317.
doi: 10.1097/CCM.0000000000005589. Epub 2022 May 18.

Renin-Angiotensin System Pathway Therapeutics Associated With Improved Outcomes in Males Hospitalized With COVID-19

Genevieve L Y Rocheleau  1 , Terry Lee  2 , Yassene Mohammed  3   4 , David Goodlett  3   5   6 , Kevin Burns  7 , Matthew P Cheng  8 , Karen Tran  9 , David Sweet  10 , John Marshall  11 , Arthur S Slutsky  11 , Srinivas Murthy  12 , Joel Singer  2 , David M Patrick  13 , Bin Du  14 , Zhiyong Peng  15 , Todd C Lee  8 , John H Boyd  1   16 , Keith R Walley  1   16 , Francois Lamontagne  17 , Robert Fowler  18 , Brent W Winston  19 , Greg Haljan  20 , Donald C Vinh  8 , Alison McGeer  21 , David Maslove  22 , Santiago Perez Patrigeon  22 , Puneet Mann  23 , Kathryn Donohoe  23 , Geraldine Hernandez  23 , James A Russell  1   16 ; for ARBs CORONA I Investigators
Affiliations
Observational Study

Renin-Angiotensin System Pathway Therapeutics Associated With Improved Outcomes in Males Hospitalized With COVID-19

Genevieve L Y Rocheleau et al. Crit Care Med. .

Abstract

Objectives: To determine whether angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors are associated with improved outcomes in hospitalized patients with COVID-19 according to sex and to report sex-related differences in renin-angiotensin system (RAS) components.

Design: Prospective observational cohort study comparing the effects of ARB or ACE inhibitors versus no ARBs or ACE inhibitors in males versus females. Severe acute respiratory syndrome coronavirus 2 downregulates ACE-2, potentially increasing angiotensin II (a pro-inflammatory vasoconstrictor). Sex-based differences in RAS dysregulation may explain sex-based differences in responses to ARBs because the ACE2 gene is on the X chromosome. We recorded baseline characteristics, comorbidities, prehospital ARBs or ACE inhibitor treatment, use of organ support and mortality, and measured RAS components at admission and days 2, 4, 7, and 14 in a subgroup ( n = 46), recorded d -dimer ( n = 967), comparing males with females.

Setting: ARBs CORONA I is a multicenter Canadian observational cohort of patients hospitalized with acute COVID-19. This analysis includes patients admitted to 10 large urban hospitals across the four most populated provinces.

Patients: One-thousand six-hundred eighty-six patients with polymerase chain reaction-confirmed COVID-19 (February 2020 to March 2021) for acute COVID-19 illness were included.

Interventions: None.

Measurements and main results: Males on ARBs before admission had decreased use of ventilation (adjusted odds ratio [aOR] = 0.52; p = 0.007) and vasopressors (aOR = 0.55; p = 0.011) compared with males not on ARBs or ACE inhibitors. No significant effects were observed in females for these outcomes. The test for interaction was significant for use of ventilation ( p = 0.006) and vasopressors ( p = 0.044) indicating significantly different responses to ARBs according to sex. Males had significantly higher plasma ACE-1 at baseline and angiotensin II at day 7 and 14 than females.

Conclusions: ARBs use was associated with less ventilation and vasopressors in males but not females. Sex-based differences in RAS dysregulation may contribute to sex-based differences in outcomes and responses to ARBs in COVID-19.

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Conflict of interest statement

Drs. Rocheleau’s, Cheng’s, Lee’s, Haljan’s, Vinh’s, Mann’s, Donohoe’s, and Russell’s institutions received funding from the Canadian Institutes for Health Research. Dr. Mohammed’s institution received funding from Genome Canada and Genome British Colombia. Dr. Goodlett disclosed that he is the founder of Pataigin LLC and Deurion LLC and that the University of Victoria Genome British Columbia Proteome Centre (for which he is a director) received funding from Genome Canada and Genome British Colombia. Dr. Burns disclosed that he is a consultant to JN Nova Pharma. Dr. Cheng’s institution received funding from McGill Interdisciplinary Initiative in Infection and Immunity; he received funding from GEn1E Lifesciences and NPlex Biosciences; he disclosed that he is the cofounder of Kanvas Biosciences and owns equity in the company; and he disclosed that he is a named coinventor on a pending patent entitled “Methods for assessing the severity and progression of SARS-CoV2 infections using cell-free DNA.” Dr. Slutsky received funding from Apeiron, GlaxoSmithKline, Baxter, Cellenkos, Diffusion, Edesa, Exvastat, Faron, and Novalung. Dr. Lee received funding from the Fonds de recherche du Quebec santé (FRQS). Dr. Haljan’s institution received funding from Michael Smith Foundation for Health Research and Surrey Hospital Foundation. Dr. Vinh’s institution received funding from the Jeffrey Modell Foundation and FRQS; he received funding from CSL Behring, Astra Zeneca, Moderna, Takeda, QU Biologics, Merck Canada, Novartis Canada, and the COVID Immunity Task Force (Public Health Agency of Canada); he disclosed he has patent applications pending (Encrypting File System Identification [EFS ID] 40101099; EFS ID 44321620). Dr. Russell reports patents owned by the University of British Columbia (UBC) that are related to the use of proprotein convertase subtilisin/kexin type 9 inhibitor(s) in sepsis and related to the use of vasopressin in septic shock and a patent owned by Ferring for use of selepressin in septic shock; he is an inventor on these patents; he was a founder, director, and shareholder in Cyon Therapeutics and is a shareholder in Molecular You Corp; he reports receiving consulting fees in the last 3 years from: Asahi Kesai Pharmaceuticals of America (was developing recombinant thrombomodulin in sepsis), SIB Therapeutics LLC (developing a sepsis drug), and Ferring Pharmaceuticals (manufactures vasopressin and developing selepressin); he is no longer actively consulting for the following: La Jolla Pharmaceuticals (developing angiotensin II; Dr. Russell chaired the Data Safety Monitoring Board of a trial of angiotensin II from 2015 to 2017), PAR Pharma (sells prepared bags of vasopressin); and he reports having received an investigator-initiated grant from Grifols (entitled “Is HBP a mechanism of albumin’s efficacy in human septic shock?”) that was provided to and administered by UBC. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Figures

Figure 1.
Figure 1.
Males experience significantly worse clinical outcomes compared with females overall. Forest plot indicating results of separate regression analyses in form of multivariable logistic regression for binary outcomes (adjusted odds ratios) and Cox regression for “time to” outcomes (adjusted hazard ratios), as well as 95% CIs (x-axis), comparing males and females overall. Vertical dashed line indicates adjusted odds ratio of 1. See Methods for list of adjustment variables.
Figure 2.
Figure 2.
Prehospital angiotensin receptor blockers (ARBs) show protective effects within males: use of ventilation and vasopressors were significantly less than males not on prehospital ARBs or angiotensin-converting enzyme inhibitors (ACEi), and the effect was significantly greater than within females. Forest plot showing within sex comparison odds ratios/hazard ratios of clinical outcomes for those on ARBs (first column), ACEi (second column), or on either ARBs or ACEi (third column) versus those not on ARBs or ACEi, respectively. See Methods for list of adjustment variables. Test for homogeneity p values are included, indicating comparisons where males were significantly different than females.
Figure 3.
Figure 3.
There were varying effects of angiotensin receptor blockers (ARBs) compared with ACE inhibitors (ACEi) within different sexes. Males on ARBs had significantly shorter time to discharge compared with males on ACEi, whereas females on ARBs were significantly more likely to use ventilation than females on ACEi. Forest plot showing within sex comparison odds ratios/hazard ratios of clinical outcomes for those on ARBs versus those on ACEi. See Methods for list of adjustment variables. Test for homogeneity p values are included, indicating the protective effect of ARBs compared with ACEi was significantly greater among males compared with among females, in use of ventilation and use of vasopressor outcomes.
Figure 4.
Figure 4.
Males’ renin-angiotensin system (RAS) component levels compared with those of females hospitalized with COVID-19 at baseline (day 0), day 2, 4, 7, and 14. A, Baseline adjusted median difference in RAS component levels males versus females based on quantile regression adjusting for age, chronic cardiac disease, chronic kidney disease, diabetes, and hypertension (n = 46). B, Comparison of RAS component levels between sexes over time based on adjusted quantile regression (day 0) and linear quantile mixed regression (day 2 and onward; unable to adjust for other variables due to small sample size). ACE = angiotensin-converting enzyme.
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Comment in

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