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[OHDSI COVID-19] Review on the effect of ACE inhibitors and Angiotensin Receptor Blockers on COVID-19 incidence and complication rate

(Patrick Ryan) #1


One of the priority questions that we’ve heard from various stakeholders, including the FDA and EMA, is to understand implications of the ACE-2 pathway, which can serve as an entry point for COVID-19 and is also upregulated by ACE inhibitors and Angiotensin Receptor Blockers (two commonly used classes of hypertensive treatments).

ACC/AHA issued the following statement last week: https://www.acc.org/latest-in-cardiology/articles/2020/03/17/08/59/hfsa-acc-aha-statement-addresses-concerns-re-using-raas-antagonists-in-covid-19

But nonetheless, some clinicians and patients are considering stopping ACE inhibitor therapy due to the posited effect.

In our OHDSI collaborative efforts, we will design and execute studies to produce real-world evidence about the comparative effects of ACE inhibitors and ARBs vs. other antihypertensives for incidence of viral disease and risk of viral complications. @SCYou, @msuchard, @hripcsa and others have already made great progress toward offering a series of study designs to address this, which can be be applied to past viral models (e.g. influenza) and then applied to current and future Covid-exposed patients. But to do so, we need to have proper context around what is known biologically about this potential association, and what (if any) data exists to support or refute an association.

@conovermitch has offered to lead this review and evidence synthesis effort. If others want to join him, please use this Forum thread to get started and let’s see how far we can get by end of Wednesday. Wherever we are by then can serve as the input to the Study-a-thon workstream on this topic.

(Ana Szarfman) #2

Thanks Patrick. This is an important project

(Nicole Pratt) #3

Hi Patrick, this topic is a high priority for us here in Australia. Would love to be involved in this stream. The link below was informative.
Thanks Nicole

(Patrick Ryan) #4

Thanks @Nicole_Pratt, this is a great article to get started with for anyone who wants to understand the topic. And yes, I’m definitely counting you in on the ACE estimation subteam:) Thanks for your participation!

(daniel morales) #5

Colleagues, the Spanish and Italian medicines agency have both recently released a communication about this too. Have been considering approaches to the design and happy to support.

(Conovermitch) #6

Hey everyone, thanks for posting the useful content. I’m still in the process of doing some early reading and wrapping my head around this. In the next couple hours, my goal is to do some initial reading then draft a search strategy for pubmed / Google Scholar which I’ll post here in case anyone wants to tweak it. In the mean time, feel free to post any and all information in the thread. I’m also going to post a collaborative document that we can start populating with the information that is out there in the peer-reviewed and non-peer reviewed literature. I’ll post again soon.

(Conovermitch) #7

If anyone needs the English translation for the above article I’ve attached it below.

AIFA specifications on Covid.docx (14.9 KB)

(Conovermitch) #8

Posting a link to a Google spreadsheet which I’m hoping we can populate for each of the studies we include in our literature review. This was thrown together pretty quickly but given how quickly we are trying to finish this literature review (by Wed) I thought it was important to post this now. Please feel free to revise the spreadsheet (e.g. add columns for additional information you think we should abstract) and I’ll do my best to fill in any blank spots.

I think in the interest of time, my next steps will be to go through the works cited lists for the references everyone shared and drop anything that looks relevant into the spreadsheet. Anyone who wants to start reviewing can do so by entering their name in the “Reviewer” column next to a specific entry.

(Nicole Pratt) #9

Thanks @conovermitch. Another nice review is here http://www.nephjc.com/news/covidace2
I checked the references in the table in this document and the ones that you do not have in your LitReview spreadsheet only examine hypertension as a risk factor rather than specific hypertension treatments. Are we only interested in ACE/ARB for this review or hypertension treatments more generally?

(Conovermitch) #10

Thanks @Nicole_Pratt for checking over the spreadsheet and for sharing the reference. I’m glad we already have most of their citations accounted for. My current understanding of the plan is that there will be estimation studies comparing ACEs and ARBs against other hypertension treatments. So I think it’s a good idea to include all hypertension treatments in the literature review as long as the paper is talking about their relationship with incidence and/or complications of viral disease.

Again, feel free to make revisions to the spreadsheet if you think it needs any. I think this literature review will include a diverse set of studies (e.g. cell studies, human studies) as well as commentaries and letters. I’m still thinking through what specific pieces of information / features we want to abstract from cellular studies, commentaries, etc.

(Conovermitch) #11

Hey everyone. Just wanted to post a couple updates on the current progress.

  • If you see the Google Doc linked above you’ll see that the list of potentially relevant studies is growing pretty quickly. As was expressed in the statements by various academic societies this week, there is very little literature describing any sort of causal analyses (observational or randomized) of the relationship between antihypertensive medications and viral incidence / complications. However, over the past 12 hours, I’ve learned that there is an extensive history of possibly relevant cellular studies that describe how coronaviruses interact with the ACE-2 receptor, much of which relates to SARS-CoV and MERS-CoV.

  • Given the short turnaround we have for this literature review, I don’t want anyone getting lost trying to parse the cell studies. If you sign up to review one of those, do your best to document the main findings and conclusions. There are several commentaries on the list which have already done a nice job synthesizing the existing evidence from cellular studies on how caronaviruses bind with receptors in human (and animal) hosts. We will definitely need to lean heavily on those existing summaries in order to provide some meaningful synthesis of evidence by tomorrow night.

  • I’m going to switch gears right now away from searching and start reviewing some articles in more detail. Obviously if anyone finds any relevant citations that are not in the list, feel free to add them.

If anyone has any questions feel free to email me or reach out to me on Microsoft Teams (mconove1@its.jnj.com)


There is another viewpoint out in JAMA, but probably no surprising finding/conclusion:
COVID-19 and Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor BlockersWhat Is the Evidence?

(Conovermitch) #13

Thanks for posting @NKolb. It’s been added to the spreadsheet.

(Conovermitch) #14

Hey everyone - we’ve been making forward progress on populating the study abstraction sheet (thanks @Nicole_Pratt for all your work). As I’ve been populating the sheet, I’ve started drafting a rough outline of how to tie all of this information together (see Google Doc link below). This is still incomplete since it only includes the studies I abstracted. Hoping to work more on it this afternoon and tonight. In the meantime, anyone is welcome to add/delete/revise as much as they like.


(Conovermitch) #15

The studies that @Nicole_Pratt abstracted have now been incorporated into the write-up / outline (linked above).

(Keesvanbochove) #16

Hi everyone,

As posted by @CSung in Research questions that the OHDSI community can potentially answer to suport the COVID-19 response, there’s also a hypothesis that AT1R blockers / angiotensin 2 such as losartan or valsartan can have a beneficial/protective effect. Since these are common medicines for treatment of a.o. hypertension, there is a chance that we can see this effect in action if we can identify these subgroups. Is this something we can assess in the study-a-thon?

See https://doi.org/10.1002/ddr.21656 and there’s also a nice explainer video of the biochemistry which I have to look up,



(Conovermitch) #17

Hey @keesvanbochove . Thanks for sharing. The good news is that we have already incorporated the article you linked (Gurwitz et al. 2020) into the literature review spreadsheet and the text write-up / outline - both of those are linked above. Gurwitz et al is not the only one to propose mechanisms whereby ACEs and ARBs may have different effects on the SARS-CoV-2 cellular attachment process. So I agree with that there would be value to producing evidence that considers ACE’s and ARBs separately (instead of just a comparison of ACE/ARB vs. calcium-channel blockers).

(vaishali popat) #18

Patrick and team,
Thank you for this important effort.

(Conovermitch) #19

Hey everyone,

We have now moved the two google docs above (the lit review spreadsheet and the lit review text write-up) over to the “Files” tab in the “Study-Estimation-Ace Inhibitors” Microsoft Teams channel (so the two google docs linked above are no longer active). If you want to collaborate/contribute and you are on the study-a-thon team, please find them there. If anyone has any trouble finding these documents please reach out to me on Teams or by email (mconove1@its.jnj.com)

A spreadsheet containing information abstracted from key references has been posted to the “Files” tab in the “Study-Estimation-Ace Inhibitors” channel on Microsoft Teams (link below).

  • Filename: Literature Review - ACE_ARB and COVID-19 incidence and complications.xlsx

The literature review text write-up has been incorporated into the Main Document file which is also available in the “Files” tab in the “Study-Estimation-Ace Inhibitors” channel on Microsoft Teams (link below).

  • Filename: MAIN DOCUMENT – ACEi Estimation


(Geert Byttebier) #20

Can it still be useful to add in this workpackage literature on the possible role of statins either alone or in combination with ARBs ? Has article below already been added to the list ? Thank you.

mBio. 2020 Mar 20;11(2). pii: e00398-20. doi: 10.1128/mBio.00398-20.

Hiding in Plain Sight: an Approach to Treating Patients with Severe COVID-19 Infection.


Patients with COVID-19 infection are at risk of acute respiratory disease syndrome (ARDS) and death. The tissue receptor for COVID-19 is ACE2, and higher levels of ACE2 can protect against ARDS. Angiotensin receptor blockers and statins upregulate ACE2. Clinical trials are needed to determine whether this drug combination might be used to treat patients with severe COVID-19 infection.