New Paper (Other): Association of Renin-Angiotensin System Inhibitors With Severity or Risk of Death in Patients With Hypertension Hospitalized for Coronavirus Disease 2019 (COVID-19) Infection in Wuhan, China

[dziakj1]

Title: Association of Renin-Angiotensin System Inhibitors With Severity or Risk of Death in Patients With Hypertension Hospitalized for Coronavirus Disease 2019 (COVID-19) Infection in Wuhan, China

General Information

Please paste a link to the paper or a citation here:

Link: https://jamanetwork.com/journals/jamacardiology/fullarticle/2765049

What is the paper's Manubot-style citation?

Citation: @doi:10.1001/jamacardio.2020.1624

Is this paper primarily relevant to Background or Pathogenesis?

• [ ] Background
• [x] Pathogenesis
• [ ] Methods

Please list some keywords (3-10) that help identify the relevance of this paper to COVID-19

• renin-angiotensin system inhibitors
• angiotensin receptor blockers
• hypertension

Please note the publication / review status

• [ ] Pre-print
• [x] New Peer-Reviewed Paper
• [ ] Peer-Reviewed Paper Pre-2020

Which areas of expertise are particularly relevant to the paper?

• [ ] virology
• [ ] epidemiology
• [ ] biostatistics
• [ ] immunology
• [x] pharmacology
• [ ] other:

[dziakj1]

Summary

This is a brief report in JAMA Cardiology.

Suggested questions to answer about each paper:

• What did they analyze? "Retrospective, single-center case series of the 1178 hospitalized patients with COVID-19 infections at the Central Hospital of Wuhan, China, from January 15 to March 15, 2020." Of them, 362 had hypertension, and 115 were taking ACEI/ARB medication for hypertension.

• What methods did they use?

They were a bit vague. The results were generally two-group comparisons, "using the Mann-Whitney U test, t test, χ2 test, or Fisher exact test. A 2-sided α of less than .05 was considered statistically significant." The absence of multiple comparison correction is okay here because the negative findings are the point. The study is entirely observational and there is apparently no attempt to control for covariates, so it is not possible to rule out some kind of confounding or suppressor variable.

• Does this paper study COVID-19, SARS-CoV-2, or a related disease and/or virus?

Specifically COVID-19

• What is the main finding (or a few main takeaways)?

The authors say their results suggest that "ACEIs/ARBs are not associated with the severity or mortality of COVID-19 in such patients," so "These results support current guidelines and societal recommendations for treating hypertension" (i.e., patients can keep taking these drugs and don't have to stop taking them if they become infected).

• What does this paper tell us about the background and/or diagnostics/therapeutics for COVID-19 / SARS-CoV-2?

The authors were addressing concerns that since ACE2 expression may increase risk and severity of COVID-19, a drug which inhibits angiotensin-converting enzyme might be considered dangerous. But they say they find no evidence for this. I do not know enough about cardiology or pharmacology to evaluate their claims.

• Do you have any concerns about methodology or the interpretation of these results beyond this analysis?

It's impossible to prove a null hypothesis, but the authors seem to make a good case that these drugs are not something to worry about in this context. As a caveat, I am not an expert on any of these topics and not familiar with cardiology, so I cannot be sure that I understand what they are saying. The paper in issue #325 also briefly recommended similar null findings.

[matfax]

The problem in the Angiotensin axis is, howsoever they decide to intervene in the natural expression of ACE2, it always has an inverse secondary effect. Decreasing free ACE2 (e.g. by altering ANG2) inhibits cell fusion but also enhances virus-mediated morbidity. Increasing free ACE2 inhibits virus-mediated morbidity but also enhances cell fusion and hence a delayed morbidity that is mediated by the accelerated infection progress. Altering ANG2 has short and long term effects, moreover, so it's not a quick ARB change that will make a difference. Based on this knowledge, I would hypothesize that it depends on baseline Angiotensin status and the phase of infection/viral load (incubation vs. mild vs. severe infection) for ARBs to improve overall disease severity. But this is very impractical, especially for patients who depend on ARBs already. The challenge is to find hypertension therapeutics that do not intervene in free ACE2 expression but keep the ANG2/ANG1-7 ratio-mediated effects balanced in other ways, e.g. by use of subsequent receptor blockers (especially AT1) or Mas activators. AT1 blockers might also increase ANG2 levels, however, and thereby alter ACE2 again in the mid-term. Furthermore, study designs have to include a long adaptation phase for the ACE2 expression to adapt to the new medication if they randomize it. This is also impractical given the current circumstances.