SCCM Resource Library-ARBs and ACE Inhibitors Are Associated With Improved Outcomes in Males Hospitalized With COVID-19

Video Transcription

So, hello and welcome. My name is Genevieve Droshlo, and I come all the way from Vancouver, BC, Canada. And so here's a little blurb about myself.  I conducted a master's in experimental medicine at UBC investigating HIV drug resistance. I then went on to work for UBC as a project manager for clinical trials, which was how  I came into ICU research. I then ran off to Ireland kind of mid-pandemic, which is actually where I am now giving this  talk, and I ran off to attend medical school, but then returned back to Vancouver in 2021 to perform this research that I am so very excited to share with you today.  So today I'll be discussing our prospective observational research on the use of ARBs  or angiotensin receptor blockers among hospitalized COVID-19 patients, and how males in particular seem to experience clinical benefits from this drug.  So you'll notice the original title includes ACE inhibitors, so let me just fix that. So when we originally submitted, ACE inhibitors played a more dominant role.  However, we have since had reviewer feedback, and I want to present the most up-to-date and best version of our work.  As we all know, especially over the last two years, the nature of science is constantly evolving.  I just want to take a moment to give a nod to all the scientists working on COVID-19 and their incredible adaptability during these times. I am constantly amazed.  Anyway, sorry for the aside, I'm moving on to the current title of this talk, which is ARBs are associated with improved outcomes in males hospitalized with COVID-19.  So it's been widely reported that biological sex plays a role in COVID-19. Specifically, biological males seem to fare worse than females, and this is born out in the data.  We're comparing Canadian data aggregated by the Global Health 50-50 Research Initiative. You can see that males have about the same number of confirmed cases, but once infected,  males will proceed to experience proportionally more hospitalizations and ICU admissions. However, one interesting aspect you can see here on the slide is that there's no difference  in mortality between sexes, and actually this trend is seen in other developed countries as well.  In fact, globally, males do die more often from COVID-19 than females. However, the trend shown on the slide is accurate for developed countries like Canada and the  United States as well. So now that we've established that males do in fact fare worse than females in COVID-19, one of the questions we asked was why.  Well, we think that renin-angiotensin system pathway plays a role. So this pathway is your body's natural blood pressure regulator, as you probably well know,  and SARS-CoV-2 actually binds to ACE-2 to gain cell entry. So ACE-2 is a key receptor enzyme in this pathway, and here in this image it's shown in blue in the center there.  SARS-CoV-2 actually causes downregulation of ACE-2 expression on host cell surface, but at the same time activates this RAS pathway.  So since the role of ACE-2 is to cleave angiotensin-2, thereby deactivating it and converting it to angiotensin was seven there on the left.  The net effect of having ACE-2 kind of downregulated by SARS-CoV-2, this net effect is to have this buildup of angiotensin-2 because there's nothing to cleave it.  So angiotensin-2 is this pro-inflammatory molecule in circulation, and it leads to increasing inflammation and organ damage.  And these are critical contributors to mortality in acute COVID-19. We think that drugs like ARBs could block angiotensin-2 receptors in other organs of  the body like the heart and kidney with their high levels of expression of ACE-2, protecting them from greater angiotensin-2-associated damage.  Interestingly, ACE-2 gene is located on the X chromosome and therefore may play a role in the sex differences that we've seen in clinical status, however this is speculation.  So these are a priori hypotheses we submitted to the CIHR, which is the Canadian version of the NIH. And we submitted these about two years ago.  We proposed that RAS pathway dysregulation and SARS-CoV-2 play a role in the sex differences  observed in clinical outcomes, and that ARBs are associated with improved clinical outcomes in hospitalized COVID-19 patients according to sex.  So in order to test these theories, we set up a multi-site cohort called ARBsCorona1. The project collects information on patients over 18 years of age who are admitted to hospital  primarily for COVID-19, and there are no exclusion criteria. So 10 hospital sites across four of the largest provinces participated between February 2020  and April 2021, and 1,686 patients were included in our final cohort here. So to test RAS pathway dysregulation, we also actually collected leftover plasma samples  from admission and days 2, 4, 7, and 14 of their hospital stay. These were used for a proteomics analysis, which due to time limitations, we're not going  to be discussing here today, but we do have a paper coming out. So please stay tuned on that one.  So outcomes were recorded according to our World Health Organization Ordinal Scale for COVID-19.  So we felt that this allowed for a more nuanced understanding of clinical status, particularly for ICU care workers, such as you find people.  So because this Ordinal Scale, it uses practical outcomes for organ support, like mechanical ventilation, need for vasopressors, and need for renal replacement therapy, as opposed  to just reporting epidemiological data like ICU admission and death, which are commonly reported.  We hope that ICU care workers will therefore find this research more helpful in the actual treatment of severe COVID-19.  However, we also included 28-day mortality, as this is standard across the field. In terms of analyses, we conducted adjusted logistic regression analyses for binary outcomes,  like on a ventilator versus no ventilation needed, as well as adjusted Cox regression for analyses that are time to outcomes, like time to discharge.  So this is a quick overview of our cohort. After data cleaning, for example, exclusion of readmissions and where sex was not specified in the data, we ended up with 1,686 patients.  The median age of our cohort was 67 years, and there were 61% males and 39% females.  64% are on neither ARBs or ACE inhibitors, and 18% were on ARBs and ACE inhibitors, respectively.  For comorbidities, we recorded a lot of different comorbidities, but these were the four most commonly associated with severe COVID-19, and were therefore adjusted in our models.  So this includes chronic cardiac disease, chronic kidney disease, hypertension, and diabetes.  And this is actually a really important step, since many of the individuals who would be on ACE inhibitors or ARBs would have one of these comorbidities, and these actually put  you at much greater risk for severe COVID-19. So we could have a compounding factor within our data, so it was really important that we adjusted for these.  There was also only about 2% of our cohort testing positive for other pathogens, so we're fairly sure the results are relatively unbiased in that regard.  The enrollment timeline right up at the right upper corner there shows proportions of roll  over time, and we were able to comprehensively capture the first two waves of the pandemic.  And then at the bottom right, it shows enrollment across the four main provinces, and you can see that BC was a big player there, as we were the coordinating site.  So this is a direct comparison of females to males. In this figure, we wanted to show that A, our cohort is representative of Canada, and  that males do have worse outcomes than females, and B, we also wanted to provide a little more nuance in the clinical outcomes, as I mentioned before.  So each of the outcomes listed on the left represents an individual adjusted analysis comparing males to females for that particular outcome.  And so there was no difference in mortality, use of renal replacement therapy, or time to hospital discharge between females and males.  However, admission to IC was significantly greater in males, and I think this shows that  this cohort is fairly representative of COVID-19 in Canada, as it reflects that epidemiological data I showed you earlier.  And in regards to showing more nuanced clinical outcomes, we also found that males needed  invasive ventilation and vasopressors significantly more than females, so they tend to be much sicker. So next we did a similar comparison for ARBs.  Males on ARBs were compared to males not on ARBs or ACE inhibitors, and the same comparison was done within females.  Next we compared the results between the sexes using a test for interaction, and that's the p-values that you see on the side there.  So test for interaction was significant in need for ventilation and need for vasopressors.  In summary, males who were on ARBs were less likely to need invasive ventilation or vasopressors  compared to males who were not on ARBs, and that's the blue you can see on the left-hand side of the dashed line. In females, this effect was not observed.  So for invasive ventilation and for vasopressors, you see the error bars of the red overlapping that dashed line.  And therefore, this difference between sexes was significant, and it shows a meaningful difference in clinical status associated with taking ARBs, thereby supporting our a priori  hypothesis. I'll also point out that for ACE inhibitors alone, none of these results were significant.  So based on these findings, we conclude that males hospitalized with acute COVID-19 experience  greater risk of ICU admission, need for ventilation, and need for vasopressors compared to females.  We also found that ARBs use was associated with less need for ventilation and vasopressors in males, but not in females.  And perhaps ARBs, therefore, may actually help address the sex disparity in outcomes among hospitalized COVID-19 patients.  So I want to acknowledge Jim as the lead PI and my co-investigators for their collaboration and support. Terry, for writing our statistics and helping generate figures.  Our funders, the Canadian Institutes for Health Research and the St. Paul's Hospital Foundation.  A special thank you to the ARBs Coroner 1 investigators, research staff, and clinical staff treating these patients, and to the patients and their families for making this  work possible. Thank you very much.

Video Summary

Genevieve Droshlo, a researcher from Vancouver, BC, Canada, conducted a study on the use of ARBs (angiotensin receptor blockers) among hospitalized COVID-19 patients. The study found that males, who generally fare worse than females in COVID-19, experienced clinical benefits from taking ARBs. The research suggests that the renin-angiotensin system pathway plays a role in the sex differences observed in COVID-19 outcomes. ARBs, which block angiotensin-2 receptors, may protect organs from angiotensin-2-associated damage. The study concludes that ARBs may help address the sex disparity in COVID-19 outcomes. The research was conducted as part of the ARBsCorona1 cohort, which collected data from 1,686 patients across 10 hospital sites in Canada.

Asset Subtitle

Crisis Management, Pharmacology, 2022

Asset Caption

INTRODUCTION/HYPOTHESIS: SARS-CoV-2 spike protein binds and down-regulates angiotensin-converting enzyme 2 (ACE2), possibly increasing angiotensin II (pro-inflammatory). ACE2 is on the X chromosome and males account for more ICU admissions and deaths. We propose sex-differences in renin-angiotensin system (RAS) peptides contribute to sex disparity and use of ARBs or ACEi is associated with greater improvement in clinical outcomes in males than females hospitalized with COVID-19.
METHODS: ARBs CORONA I is a multisite Canadian cohort study of hospitalized COVID-19 patients. We recorded baseline characteristics, comorbidities, pre-hospital/hospital treatment with ARBs/ACEi, ICU admission, use of ventilation, vasopressors, renal replacement therapy (RRT) and mortality. We compared the effects of ARBs/ACEi versus no ARBs/ACEi in males versus females. RAS peptides (ELISAs) and proteomics (169 proteins) were measured at hospital admission (day 0) and days 2, 4, 7 and 14 (subgroup; n=46). Multivariable Cox regression determined adjusted hazard ratio for time to outcomes. Multivariable logistic regression determined adjusted odds ratio of outcomes according to sex and ARBs/ACEi treatment.
RESULTS: We included 1687 patients (02/20 to 04/21). Males had significantly greater adjusted odds of ICU admission (aOR=1.42, p=0.008), ventilation (aOR=1.45, p=0.006), and vasopressors use (aOR=1.46, p=0.005) compared to females. Among males on either ARBs or ACEi, there was significantly less ventilation (aOR=0.62, p=0.012), vasopressors (aOR=0.67, p=0.032) and RRT (aOR=0.52, p=0.041), compared to males not on ARBs/ACEi. No significant effects were observed in females with exception of significantly earlier time to discharge on ARBs/ACEi compared to females not on ARBs/ACEi (aHR=1.25, p=0.038). Angiotensin II was higher in males (median=109 pg/ml) compared to females (median=66 pg/ml) on day 7 (p=0.048), as was day 0 ACE (adjusted median difference=78.1 ng/ml, p=0.042). In longitudinal analysis, thrombospondin-1 (p=0.00025) and matrix metalloproteinase-9 (p=0.012) were significantly higher in females than males.
CONCLUSION: Males hospitalized with COVID-19 had significantly better responses to ARBs/ACEi compared to females. Sex-based dysregulation of RAS may contribute to sex-based differences in outcomes and responses to ARBs/ACEi.

Meta Tag

Content Type Presentation

Knowledge Area Pharmacology

Knowledge Area Crisis Management

Knowledge Level Intermediate

Knowledge Level Advanced

Membership Level Select

Tag Pharmacology

Tag COVID-19

Year 2022

Keywords

Genevieve Droshlo

ARBs

COVID-19 outcomes

sex differences

renin-angiotensin system pathway

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