Renin-Angiotensin System Pathway Therapeutics Associated With Improved Outcomes in Males Hospitalized With COVID-19*,Critical Care Medicine

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Renin-Angiotensin System Pathway Therapeutics Associated With Improved Outcomes in Males Hospitalized With COVID-19*
Critical Care Medicine ( IF 7.7 ) Pub Date : 2022-09-01 , DOI: 10.1097/ccm.0000000000005589
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} ,

Affiliation

Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.
Centre for Health Evaluation and Outcome Science (CHEOS), St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.
University of Victoria, Genome BC Proteomics Centre, Victoria, BC, Canada.
Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands.
Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada.
International Centre for Cancer Vaccine Science, University of Gdansk, Gdansk, Poland.
Division of Nephrology, Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.
Divisions of Infectious Diseases & Medical Microbiology, McGill University Health Center, McGill's Interdisciplinary Initiative in Infection and Immunity, Montreal, QC, Canada.
Division of General Internal Medicine, Vancouver General Hospital and University of British Columbia, Vancouver, BC, Canada.
Division of Critical Care Medicine, Vancouver General Hospital, Vancouver, BC, Canada.
Department of Surgery, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada.
British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
British Columbia Centre for Disease Control (BCCDC), and School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
Medical ICU, Peking Union Medical College Hospital, Beijing, China.
Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
Division of Critical Care Medicine, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.
University of Sherbrooke, Sherbrooke, QC, Canada.
Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
Departments of Critical Care Medicine, Medicine and Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada.
Department of Medicine, Surrey Memorial Hospital, Surrey, BC, Canada.
Mt. Sinai Hospital and University of Toronto, Toronto, ON, Canada.
Department of Medicine, Kingston General Hospital and Queen's University, Kingston, ON, Canada.
Black Tusk Research Group Inc., Vancouver, BC, Canada.

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.

中文翻译：

肾素-血管紧张素系统通路治疗与 COVID-19 住院男性的预后改善相关*

目标：

确定血管紧张素受体阻滞剂 (ARB) 或血管紧张素转换酶 (ACE) 抑制剂是否与不同性别的 COVID-19 住院患者的预后改善相关，并报告肾素-血管紧张素系统 (RAS) 成分中与性别相关的差异。

设计：

前瞻性观察性队列研究，比较 ARB 或 ACE 抑制剂与无 ARB 或 ACE 抑制剂对男性和女性的影响。严重急性呼吸系统综合症冠状病毒 2 下调 ACE-2，可能会增加血管紧张素 II（一种促炎性血管收缩剂）。RAS 失调的性别差异可能解释了对 ARB 反应的性别差异，因为ACE2基因位于 X 染色体上。我们记录了基线特征、合并症、院前 ARB 或 ACE 抑制剂治疗、器官支持的使用和死亡率，并在入院时和第 2、4、7 和 14 天测量了亚组（n = 46）中的 RAS 成分，记录了d-二聚体( n = 967)，将男性与女性进行比较。

环境：

ARBs CORONA I 是一项针对急性 COVID-19 住院患者的加拿大多中心观察队列。该分析包括四个人口最多省份的 10 家大型城市医院收治的患者。

患者：

1686 名经聚合酶链反应确诊为 COVID-19 的急性 COVID-19 患者（2020 年 2 月至 2021 年 3 月）被纳入。

干预措施：

没有任何。

测量和主要结果：

与未服用 ARB 或 ACE 抑制剂的男性相比，入院前服用 ARB 的男性减少了通气（调整后的比值比 [aOR] = 0.52；p = 0.007）和升压药（aOR = 0.55；p = 0.011）的使用。对于这些结果，在女性中没有观察到显着影响。交互作用测试对于通气 ( p = 0.006) 和升压药 ( p = 0.044) 的使用具有显着意义，表明不同性别对 ARB 的反应存在显着差异。男性在第 7 天和第 14 天的基线血浆 ACE-1 和血管紧张素 II 显着高于女性。