COVID-19: ACEIs, ARBS, and NSAIDs

April 10, 2020

Strategic Alliance Partners

Thomas Dilworth, PharmD, provides a recap of ACEIs, ARBs, and NSAIDs in patients with COVID-19.

Segment description: Thomas Dilworth, PharmD, pharmacy coordinator, infectious diseases, Aurora St. Luke’s Medical Center, provides a recap of ACEIs, ARBs, and NSAIDs in patients with COVID-19.

Interview transcript: (modified slightly for readability)

Contagion®: Thanks for joining us for another Contagion coronavirus update. Today we're joined by Dr. Thomas Dilworth, who is a member of the Society of infectious Diseases Pharmacists, and recently gave a webinar on ARBs, ACEs, and NSAIDs. He's going to be reviewing his presentation. Thanks so much for joining us. Dr. Dilworth, we're excited to have you here with us today.

Dilworth: Hi, thanks for having me.

Contagion®: Great. So why don't we just jump right in? So far what do we know about the SARS-CoV-2 virus and ACE2 receptors?

Dilworth: Well, I think the important thing to get out right from the get-go here is we really don't know a lot about any of this stuff. I mean, this virus is only a few months old. There's a lot of unknowns. What we do know about SARS-CoV-2, which is the virus that causes COVID-19 infection is that it likely uses the angiotensin converting enzyme 2 receptor (ACE 2 receptor) to gain entry into the into the human host. This is based largely on data from a previous coronavirus, SARS-CoV-1, which uses the ACE-2 receptor. There's been some in vitro cell line infection models looking at SARS-CoV-2 showing that ACE-2 is needed for the virus to gain cell entry.

But there's really no appreciable proof in humans to definitively claim that SARS-CoV-2 must use ACE-2 to enter the human hosts and there are definitely differences between SARS-CoV-1 and SARS-CoV-2. The SARS-CoV-2 spike protein is a little bit different, and some have postulated that SARS-CoV-2 could potentially enter cells independent of ACE-2. I think the jury's out right now. But the working hypothesis is that SARS-CoV-2 does require, similar to SARS-CoV-1 to utilize ACE-2 for cell entry. Then of course, this has led to this entire line of inquiry and ongoing debate about whether you should use an ACE or an ARB; whether you should stop it, whether it has therapeutic benefit, etc, as it relates to COVID-19.

Contagion®: So that kind of leads nicely into my next question, which is: what do we know so far about the ACE and ARB use and the links to increased risk first SARS-CoV-2?

Dilworth: Again, we don't know a lot. I think this is a very interesting area from a physiologic standpoint and a pharmacotherapeutic standpoint. I think we're going to see a lot of literature and study come out in the next 3 to 6 months and even 12 months on this topic. But the long story short here is we don't have any data to suggest ACE inhibitors or angiotensin receptor blockers increase or decrease someone's risk of acquiringSARS-CoV-2 nor having a bad outcome or a better outcome with the COVID-19 infection.

I think it's important to just review, you know, the renin angiotensin aldosterone system or RAS system as it as it exists in human being. There's a molecule called angiotensin that gets converted to angiotensin 1 and then angiotensin converting enzyme converts that into angiotensin 2. Angiotensin 2 can have deleterious effects in patients with diabetes, congestive heart failure and other cardiac comorbidities.

Specifically, it leads to increasing aldosterone, sodium retention water retention, and this can lead to obviously high blood pressure. ACE inhibitors and ARBs provide a check on this system and allow these people to have better long-term outcomes. But what's also interesting is if you if you accept the premise that SARS-CoV-2 binds ACE-2 there's data to suggest that that down regulates ACE-2. ACE-2 actually provides a really important check on angiotensin 2, it helps degrade that molecule into vasodilatory molecules which reduce high blood pressure. ACEs and ARBs can actually up regulate ACE-2, which is really important when you look at some of the models that have investigated this a little bit, ACE-2 could actually help mitigate some of the lung damage that happens with viral pneumonia. There is a potential to use these drugs therapeutically, but it hasn't really been born out in humans as of yet.

Contagion®: What currently are the professional societies within the United States recommending in regard to the ACE inhibitors and the ARBs?

Dilworth: That's a great question, and that's really where, I think the most important consensus is on this issue. The majority of the organizations that have weighed in on this in the United States have said continue taking ACEs and ARBs, or patients should continue taking them. That's specifically the American Heart Association, the Heart Failure Society of America, the American College of Cardiology, the American College of Physicians, and even the American Society of Pediatric Nephrology just to name a few. And there's a number of other organizations outside the US that have reached similar conclusions. I think the reason for this is twofold. One, we don't have good data, or any data really, saying that there's detriment to using these. We have really, really good data suggesting that somebody who has congestive heart failure or diabetes or other cardiac comorbidity, their long-term outcomes are vastly improved. Their mortality goes down when they take these agents. When you put both of those pieces together, it's almost a no brainer to say. Somebody who meets guideline criteria for one of these agents, they should be taking them and that includes patients who are newly diagnosed. Those who may have had COVID-19 or have COVID-19. If they're a candidate for one of these agents, they should be on it.

Contagion®: I know in your presentation you also talked a little bit about NSAIDs. This is something that I've seen in the headlines a lot lately. What do we know about using this in individuals with COVID-19?

Dilworth: Well, again, it's similar story. We don't have much data to say one way or the other. But there's definitely no data suggesting you cannot use them. I think people are scouring to find data to suggest you should or shouldn't use them. The only modicum of data that I could find was a murine model in which ibuprofen was given and shown to upregulate ACE-2. Which if up regulate that ACE-2 receptor there's a potential to increase the likelihood that SARS-CoV-2 would bind but there was also a number of positive effects in those in those mice; these were diabetic mice. Yes, it upregulated ACE-2, but it also provided a protective effect for the mice on their on the heart and on the kidney.

I think people made a bit of a leap with the ibuprofen thing. Somebody got on Twitter overseas and said we shouldn't be using NSAIDS, and like you said, there was a firestorm in the social media in the mainstream media and it led to a lot of confusion. Thankfully for us, pharmacists and clinicians, the FDA and the World Health Organization, the European Medicines Agency, they all said you can use ibuprofen. There's also a number of leading US physicians, ID physicians, Dave Aronoff, Anthony Fauci, who is advising President Trump over the course of this pandemic and even Carlos del Rio. All of these leading voices in the US infectious disease community have said you can use ibuprofen and NSAIDs in patients with COVID-19.

I think another important point to make with NSAIDs is, if you're looking for an anti-inflammatory agent, be it an NSAID or Tylenol, or acetaminophen, that decision should be made based on patient level factors, not whether or not the patient has COVID-19. There are a number of patients for whom NSAIDs are not a good idea, for patients with kidney disease and high blood pressure, patients who have had stomach ulcers in the past. Asthmatics should not take aspirin. So those are really the decisions that should be driving whether or not somebody gets an NSAID or something other than like Tylenol, if they have COVID-19.

Contagion®: Are there any ongoing studies related to you know, ACE inhibitors, ARBS, or NSAIDs that you're particularly excited about right now?

Dilworth: Yeah, there are so I queried clinical trials.gov this morning there were 12 studies that mentioned angiotensin and SARS-CoV-2. Probably the 2 that I'm most excited about were actually the 2 first entries in that list They have not started enrolling yet, but they're at the University of Minnesota, and they're looking at the therapeutic potential of losartan, which is an ARB, for hospitalized and non-hospitalized patients with COVID-19 infection compared to standard of care. I think doing that in a randomized controlled fashion will really help shed some light as to whether or not giving these agents to somebody who otherwise doesn't need them would have a therapeutic advantage or not in patients with COVID-19.

I did also query looking for NSAIDs on clinical trials.gov this morning, and there's 1 study that's not enrolling yet, but it's going to be in France, and it's going to be in critically ill patients with COVID-19. They're going to look at the naproxen, which is an NSAID, with standard of care compared to the standard of care, to see whether or not that has any impact on outcomes and critically ill patients with COVID-19. And it should be mentioned that naproxen is a unique molecule and it does have some antiviral activity, it's been shown to have some activity against influenza. So they're postulating, the investigators, that if it has some antiviral activity, combined with its anti-inflammatory activity, that there may be a potential therapeutic niche for that drug in critically ill patients with COVID-19. That's an exciting study to me.

Great, thank you so much for that.

Contagion®: My next question is actually one that we received from a member of our web webinar audience from last week. This person asked as to is involved in heart function and the development of hypertension. So is there any research involving ACE-2 drugs in the queue

Dilworth: Yeah, so I think you can answer this 1 of 2 ways. If you're looking for drugs that you know, directly, you know, direct ACE-2 work. There actually is humanized ACE-2, you can give that to a person. There's actually a small pilot studies going on in China, they're looking at humanized ACE-2 with the standard of care compared to standard of care. This is sort of a proof of concept study to see whether or not giving somebody humanized ACE-2 would have any potential benefit. You got to remember that, ACE-2 could be downregulated by SARS-CoV-2 binding, but if you gave more of it, that could help mitigate some of the damage that's caused by angiotensin 2 downstream.

I think also indirectly, like I mentioned, losartan trial at the University of Minnesota or the 2 trials you know, that sort of an indirect drug effect on ACE-2 as well. I think there's a lot of research going on. I think another thing that's important to mention is there was a pre-print publication on medRxiv, it was came out of China, it was over 500 patients with hypertension, and they clued in on about 50 patients who are elderly, over the age of 65, with hypertension, and they looked at the severity of their COVID 19 infection progression, and what antihypertensive they were on and they saw a signal a very small signal that ARBs may be protective and mitigate some of the progression of the disease. I also think we may see research like that sort of observational research hypothesis generating research that will be needed to inform more trials like the question being asked here.

Contagion®: Great. My last question related to this topic is: do you have any final thoughts or conclusions that you want to share with us from your webinar?

Dilworth: Yeah, absolutely. I think, you know, if you wanted to quick take home points, they're three-fold. Patients who are taking ACES or ARB should continue taking them. There's definitely a mortality benefit there for a reason. Patients who require NSAID therapy should take NSAIDs, even if they have COVID-19. The decision of whether or not somebody should receive an NSAID, with a concomitant COVID-19 infection should be based on patient level factors, not whether or not they have COVID-19.

I think the third point is, there's going to be a lot of research coming out in this area, we need research in this area. If it's something that you're passionate about and you're listening to this, I would encourage you to do that. Do some observational research, see what themes you can you can draw the data. Let's all try to work together to inform the research in this area and in future clinical trials in this area. I would continue to be skeptical of information that gets broadcast on social media and even the mainstream media. Really, as clinicians, you need to dig into the substance of any that's behind these claims. Use the training that you have to really evaluate whether or not these claims are true or not, because these decisions could ultimately impact patient care.

Dilworth’s webinar, presented on behalf of the Society of Infectious Diseases Pharmacists, is available here.