In episode 5 of Primary Viewpoints, Jonathan Chow, MD, reviews the landmark study findings that patients with COVID-19 taking low-dose aspirin had reduced risk for death.
The following transcript has been edited for clarity and length.
Sydney Jennings: Hello and welcome to Primary Viewpoints from Patient Care Online, a monthly podcast that features informative conversations with health care experts, opinion leaders, and practicing physicians, about what impacts primary care medicine today.
My name is Sydney Jennings and I am the Associate Editor at Patient Care Online and in our fifth episode Grace Halsey, senior editor of Patient Care Online, talks with Jonathan Chow, MD, assistant professor of anesthesiology at the University of Maryland School of Medicine, about the results of a landmark study he led and presented at the recent virtual American Heart Association Scientific Sessions 2020 that showed the dramatic impact aspirin had on morbidity and mortality among patients hospitalized with severe COVID-19.
Patient Care (PC): So, before you describe the study and the results, I know that the University of Maryland School of Medicine is involved with COVID-19 research into a potential vaccine and also potential treatments. How did your team make the decision to start looking at the potential impact of aspirin?
Dr Chow: The decision to look at aspirin was actually quite organic. Our team who was working in the COVID ICU in the springtime, we noticed that patients would have a lot of blood clots develop during their hospitalization. And I started talking with some of my colleagues at some other centers along the east coast. And we thought that aspirin might have a beneficial effect because of its anti-platelet properties. And that's how we started looking at aspirin in the first place.
PC: You've mentioned that you were talking with colleagues at other institutions, so those must have been among the hospitals—why don't you describe the study and how it went and what you found?
Dr Chow: Yeah, so our study was a retrospective study, meaning that we look back in time. And we examined 412 patients who were admitted to the hospital with COVID-19. And we took a look at their medical records. And we looked at whether or not patients had aspirin in the 7 days prior to admission to the hospital, or within the first 24 hours of hospitalization. And those patients were categorized as receiving aspirin. And then those patients who did not receive aspirin, were in the non-aspirin group.
And the 3 major outcomes that we looked at were the use of the ventilator, the use of the ICU, and in-hospital mortality. And after adjusting for multiple comorbidities, and age and ethnicity and gender, we found that patients who were taking aspirin had a significantly reduced risk of being sent to the ICU—a 43% decrease in ICU risk, a 44% decrease in the risk of ending up on a ventilator, and then, most importantly, a 47% decrease in the risk for dying in the hospital, which was quite significant.
PC: Quite significant. And since your hypothesis was that aspirin use could help prevent use of ventilator and it did, maybe that wasn't a surprise, but were you surprised by the size of the effect across all 3 measures?
Dr Chow: We weren't surprised necessarily at the result. But you are correct in that we were surprised at the effect size or the amount of decrease in those 3 major variables because that effect size is quite significant. It is approaching almost 50% in all three categories.
PC: So, there have been a number of studies or a lot of research basically on the use of aspirin in acute lung injury and prevention or treatment of acute lung injury and acute respiratory distress syndrome. And as you mentioned in the study those results have been uneven, some show a very positive effect, and some don't show any effect at all. And yet the effect of your sizes, you know, is huge. What do you think could be some of the reasons for that?
Dr Chow: Yeah, so there have been several studies in the past that have examined the use of aspirin in lung injury, specifically in ARDS. In Ehrlich and their group looked at 161 patients, Chen and their group looked at over 1000 patients who are at risk of developing a ARDS and they both found that aspirin use was significantly associated with a decrease in the incidence of ARDS.
There have been other groups such as Kor (et al) that did not find this significant association. And then most importantly, there was a randomized control trial called the LIPS-A (Lung Injury Prevention Study with Aspirin) and that looked at 390 patients who were again at high risk for developing ARDS, and they found no association between aspirin use and ARDS and improved survival. So, the main difference between our study and all of the previous studies is that we only looked at patients with COVID-19. Whereas all the other studies looked at patients who were either at high risk for ARDS or at high risk for acute lung injury, meaning that the patients that they enrolled, they had a broad range of diagnoses, they could have had pneumonia, they could have had pancreatitis, trauma, they could have aspirated. And all of those entities are not necessarily associated with a high risk of developing blood clots, as in the case of COVID-19.
PC: Right. And you also mentioned in the study that none of those diseases either are associated with hypercoagulability, which is basically what potentiates, ARDS in COVID-19.
Dr Chow: Correct. In COVID-19—we saw this everywhere in the COVID ICU, that these patients with severe COVID disease, they would develop a large burden of blood clots, which would eventually lead to multi-organ failure. And numerous studies have examined this in COVID-19. Specifically, COVID-19 is associated with three times a higher level of blood clots than all other patients in the ICU. Patients with COVID have double the amount of blood clots than patients with influenza. And then even on autopsy, investigators have found that there is a higher level of micro-clots that are in the lung heart in the kidneys; there’s an excess number of megakaryocytes, which are the precursors to platelets, which lead to blood clots that are found in these patients.
PC: Was there any excess bleeding observed in the study at all among any of the patients? That they if they if they were admitted already on aspirin, and nothing was done to change the dose then? Perhaps not?
Dr Chow: Yeah, so in our study, we took a look at overt bleeding or any kind of major bleeding. And we did not find that there is a significant difference in the rate of major bleeding between the patients who are on aspirin and the patients who are not on aspirin. And we think that this may be the case because COVID as such is a disease that is so prothrombotic, or leads to so many blood clots, that the effect of one of the risks of aspirin, which is bleeding, may be outweighed by the disease of COVID. itself.
PC: So, it's easy to think, as this group of people I spoke with yesterday, that you know, we've stumbled upon a miracle here. And what we don't want is people saying, “Oh, I will protect myself from a severe case of COVID by starting to take a daily aspirin.” I think that could be a communication issue. But so far, what we know is that if you're on aspirin, and you come into the hospital, you're going to do better. You did mention, I think in the study that patients who had aspirin started within the first 24 hours of admission also did very well.
Dr Chow: Yes. So, in the aspirin group, it was very broad. It was any patient on aspirin in the previous seven days, or patients who are started on aspirin within the first 24 hours of admission, those were the patients who were in the aspirin group.
And in our paper, we stress that although this manuscript provides very optimistic data, we need to be very cautious with this data. Because we looked back in time, we did not conduct a randomized controlled trial. So, any associations that we found in our paper do not prove causation. So, we are not recommending that patients go to their pharmacy and start buying aspirin and taking it on their own. It is very important for patients who may be interested in taking aspirin, they need to speak with their primary care doctor so that those physicians can assess the individual risks and benefits to every patient because there are risks involved, as we know with taking an aspirin
PC: Sure; I was curious about the patients who were in whom aspirin was initiated after they came in. Do you know what the reasons were for that? If they didn't come in, but then they were started on a regular course?
Dr Chow: Yeah, so these patients who were not on aspirin at home, but then were started on aspirin in the hospital. And we didn't do a formal analysis. But in general, those patients presented to the emergency department with shortness of breath. And then they received an aspirin as part of the protocol just in case they had a heart attack. And those were the patients who were primarily started on aspirin in the first 24 hours of hospitalization.
PC: And I can't remember now, but how long? What was the end point in terms of time? How long did you look at the patients?
Dr Chow: So we looked at the patients, either all the way until the end of hospitalization so that they were discharged from the hospital and went home—or they were discharged from the hospital because they did not survive their hospitalization.
PC: Right. Is University of Maryland School of Medicine planning any follow up to this? Or do you know of other maybe, well controlled clinical trials that are being designed?
Dr Chow: Yes. So, I know of 2 randomized control trials of aspirin that have been that are being conducted right now. And those studies are on clinical trials.gov. I do not know any status updates for those trials. But I do know that we are actively developing a protocol right now to submit to an IRB so that we can conduct our own randomized control trial of aspirin in COVID-19. Because I think that randomized control data will be very important to make the ultimate decision on aspirin use.
PC: It should be very interesting to see 3 years down the road now what the armamentarium for treatment of this virus actually looks like because it's beginning to feel as though it's going to be some off the shelf stuff. I mean, dexamethasone is doing a great job, aspirin may figure into the picture. And then there hopefully will be some of the investigational drugs anyway, underway now will also prove to be effective, and there could very well be a vaccine.
Dr Chow: Correct.
PC: And so just very briefly, the limitations of the study as you all understand them, and I think some of the limitations also have laid the groundwork for more research.
Dr Chow: Right, I think our study was limited by the sample size of 412 patients. So, it is a relatively small study in the grand scheme of things. And our study was an observational study. So, we did not intervene with aspirin, we just looked back in time at patient medical records to find that association. Also, patients who were in the aspirin group, they tended to have a higher number of comorbidities than patients who are not taking aspirin, which makes sense. And one possible limitation of this is that these patients who were extremely sick, they may have received different medical care due to treatment biases because they were much sicker at baseline. Also, another limitation in terms of the recording of thrombotic events, we didn't record variables such as oral contraceptives or hormone replacement therapy, both of which are associated with increased thrombus formation or increased clot formation in the body. And we also did not control for imaging, we for the detection of thrombus is that was all done at the discretion of the treating clinician. So, if a clinician had a low suspicion of a clot forming, then they probably would not get an image to confirm that. So maybe that may be a reason why we didn't detect a difference in the overall rate of major clots in patients on aspirin and not on aspirin.
PC: Right, I forgot to ask this at the beginning. But it seems that the average age of the patients in the study was fairly young—given what we know about who is at the highest risk of dying from COVID-19, and maybe age was canceled out by comorbid or preexisting conditions? I don't know. But did it seem like a fairly young group to you?
Dr Chow: So the average age in our study was about 55 years old, which does not seem, it seems right about on par with what types of patients we were seeing in the intensive care unit, especially during the Spring in our ICU. They were they were very young. I mean, we had patients who are 20-, 30-, 40-year-old who were on a ventilator and on full life support in the ICU. And that is why we need to get more data to ascertain the true effect of aspirin in this disease.