HEP-COVID Clinical Trial Results on the Prevention of Blood Clots

John Whyte, MD; Alex Spyropoulos, MD


November 17, 2021

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JOHN WHYTE: Welcome, everyone. I'm Dr. John Whyte, the chief medical officer at WebMD. And you're watching Coronavirus in Context.

One of the things that we've learned over the past 18 months about coronavirus is its impact on our blood clotting system. And we've had a lot of thoughts about what's the role of cytokine storm, what's happening with clotting.

And there's been a fascinating study just published in JAMA Internal Medicine. And I'm delighted to be joined by the lead author, Dr. Alex Spyropoulos. He is professor of medicine at the Donald and Barbara Zucker School of Medicine. Dr. Spyropoulos, thanks for joining me today.

ALEX SPYROPOULOS: It's my pleasure, Dr. Whyte. Thank you for this invitation.

JOHN WHYTE: Early on, we started to learn about the impact of coronavirus as it relates to blood clotting. And in your recent study, the Hep-COVID randomized clinical trial, really has helped shine a light on how we treat this in hospitalized patients. Can you walk us through the study?

ALEX SPYROPOULOS: Well, I'd be happy to. And this was, I have to say, a very difficult study that we undertook in the throes of the pandemic. So a very difficult randomized trial in the COVID inpatient population. So very early on, during the pandemic, if you remember the pandemic hit New York City hospitals first during the early phases, and then of course spread to the other areas of the United States. So we were one of the early health systems who bore the brunt of this early phase of the pandemic.

And what we started noticing is that patients started either developing blood clots or potentially dying from blood clots, despite being on standard doses of what we call heparin preventative medication. Heparin is a blood thinner. It's an injectable blood thinner. We've been using it for many, many years in our patients to prevent blood clots in hospitalized settings.

But what was unique and unusual and worrisome about COVID-19 was the fact that despite being on those blood thinners, patients again developed blood clots. And ultimately, a good percentage of them went on to die from complications of these blood clots. So this is what really drove us to design this randomized trial, called Hep-COVID.

JOHN WHYTE: Before we even get to the specifics of that, I want to ask you: Were you surprised that we saw issues of clotting? Here we're talking about an infectious disease, a respiratory virus. And we're having blood clots, thromboses form as a result of coronavirus. Was that shocking to you? Or did you just kind of expect it?

ALEX SPYROPOULOS: I have to say, as a thrombosis expert, it shocked me less than maybe some of my other colleagues. So we really had paid attention to earlier data, we would have seen that previous viral pneumonia, such as SARS or MERS and even H1N1, caused this phenomenon that you so nicely placed earlier in this episode of thrombo inflammation.

So it really represented a convergence of the coagulation system, the immune system, and ultimately, the inflammatory system. So almost a perfect storm of those three systems to produce blood clots in an inflammatory state, what we now call thrombo inflammation. So no, it did not surprise me as much as some of my other colleagues. And indeed, very early on in the pandemic, I was warned from colleagues, from China and from Northern Italy, that this phenomenon of blood clotting is very real and needs to be taken seriously.

JOHN WHYTE: So you decided you're going to figure out what we need to do in those patients who are hospitalized to prevent morbidity and mortality from a coagulation issue. So how did you do it?

ALEX SPYROPOULOS: Again, I have to say from the time of a blank piece of paper to the first patient randomized in the trial, was a matter of weeks. So we knew that we had to be, number one, very pragmatic in our clinical trial design, and number two, very rapid in terms of getting this up and running. So what we noted is a biomarker, right, called the D-dimer, was able to predict those patients who are hospitalized at high risk of getting complications from COVID-19. Namely, they were at increased risk of getting venous blood clots and deaths, presumably, from those blood clots.

So that's the first thing that we did. They had very elevated levels of this biomarker called the D-dimer. It predicted, again, a very high-risk population. So that's what we started with. We started with selecting a very high-risk population using this relatively new biomarker called D-dimer.

And then what we did is we randomized patients, within 72 hours of hospitalization, to receive either standard doses of heparin prophylaxis, like we've been using for almost 3 decades now, versus therapeutic or treatment doses of the same heparin. So these are much higher doses of the heparin. It was a randomized trial, and again conducted in 12 academic centers in the United States with this study design.

JOHN WHYTE: And what did you find?

ALEX SPYROPOULOS: What we found was, quite surprisingly, was that patients who were randomized to the treatment dose arm, especially as long as they were not in critical care settings, we reduced major blood clots and death by about 50% -- so 50% reduction of the risk of major blood clots and deaths in those non-ICU or non-critically ill patients. Conversely, in the critically ill population, we found essentially no differences in terms of treatment effects between those patients randomized to the standard arm or standard heparin arm, versus the therapeutic dose arm.

So this was quite surprising. And then lastly, I think importantly on the safety side, because we have to look at both, there appeared to be no price to pay in terms of increased bleeding signal. So not only was the risk of major blood clots and death reduced by 50%, but this did not appear to come at a price of increased bleeding, at least in the non-ICU or non-critical population.

That's an important point. Whereas in the ICU population, it was very different. Not only was there no treatment effect, but the risk of major bleeding was increased almost seven-fold.

JOHN WHYTE: Is it a matter, you think, of being too late in terms of the impact on the body's coagulation cascade? What do you think is going on there? That timing seems to be important.

ALEX SPYROPOULOS: It's absolutely critical. So what we think -- and again this is just conjecture -- but what we think is by the time a patient is so sick to be critically ill from COVID-19, the horse is out of the barn. They're so far advanced in the throes of what you describe before cytokine storm and the hyperinflammatory state, that simply dialing up the heparin dose or the blood thinner dose does nothing to reduce that risk, but of course, exposes the patient to harm in terms of increased bleeding. So that was the key. And if we give that therapeutic dose of heparin early on in the first 72 hours as they're being admitted to the hospital, as long as that patient is not critically ill, that would have a major impact in outcomes.

JOHN WHYTE: But is it a matter of dosing? Because many patients, when they are admitted to the hospital, do get low-molecular heparin. Sometimes they have compression, stockings placed on them, or boots. What's the main difference here, for most listeners to hear? Is it timing? Is it dosing? What are the key factors, in terms of this intervention?

ALEX SPYROPOULOS: Yeah, there are three key factors that I want to emphasize. Number one: Timing, as we said before. Because it does appear that if we're going to give higher doses of heparin, we need to do it very early on in hospitalization. Number two: Dosing. There were some earlier trials that suggest that if you give intermediate doses of heparin, again, you don't get the treatment effects that you would hope for if you give therapeutic doses of heparin.

So yes, dosing is important. In other words, if you're going to give an aggressive strategy, you have to really, really give treatment therapeutic doses of the heparin. And then, lastly: What we call the theratropic effects or potential theratropic effects. So in addition to being a blood thinner, heparin has a lot of other properties. And potentially, there may be anti-inflammatory properties of heparin, especially given in treatment or therapeutic doses that, may again, dampen this hyper inflammatory or cytokine storm response that we see in very sick, hospitalized COVID-19 patients -- so likely all three elements.

JOHN WHYTE: Since I have you here, if I may, you are a thrombosis expert. We hear lots of discussions around the Johnson & Johnson vaccine, the AstraZeneca vaccine, about thrombosis, clotting that we know, in terms of coronavirus, can cause these issues as you're describing. How do we put it into context for patients in terms of that risk of bleeding issues -- whether it's clotting or bleeding too much?

ALEX SPYROPOULOS: Well, I would say look at the numbers. The numbers don't lie. So the risk of developing a major blood clot from the Johnson & Johnson vaccine is roughly 1 in 1.3 million, roughly.

JOHN WHYTE: What are we counting as a major blood clot -- pulmonary embolus?

ALEX SPYROPOULOS: Yeah, all exactly right. So a blood clot in your lungs, a major blood clot in your legs, a major blood clot in the venous system of your brain, what we call a cavernous sinus thrombosis. So those are major blood clots that have potential to go on and cause major adverse effects, including death.

JOHN WHYTE: Give us that number again.

ALEX SPYROPOULOS: So about 1 in 1.3 million -- as a matter of fact, what I've said before is that you're more likely to be struck by lightning not once, but twice, than to get what we call vaccine-induced thrombosis, thrombocytopenia. Now on the other side of the equation, if you're a hospitalized patient over 50 years old, the chances of you developing these same major blood clots from COVID is about 1 and 100.

So put the numbers together. One in about 1.3 million, versus one in 100. I think it's fairly straightforward.

JOHN WHYTE: Is the Hep-COVID trial going to change how we treat patients with COVID when they're hospitalized?

ALEX SPYROPOULOS: Well, no single trial in and of itself will change clinical practice. But I think when you put the results of the Hep-COVID with some other trials together -- one is the very large multi-platform trial that was also published -- they were looking at a slightly different question to be answered. Both of the trials in the non-critically ill population showed that therapeutic heparin was successful in reducing, in Hep-COVID's case, what we call macro-vessel, large blood clots and death, and in the multi-platform trials, disease progression from COVID and organ failure from severe COVID-19. So when I think you put the data together in addition to some other recent publication that suggests that again, in non-critically ill patients, therapeutic dose heparin has potential to reduce all-cause mortality, then I think the picture is clear that therapeutic-dose heparin likely should be considered the new standard of care for primary prevention of blood clot and complications and deaths in non-critically ill COVID-19 patients.

JOHN WHYTE: Dr. Spyropoulos, I want to thank you for helping educate us about how we need to change the paradigm in treating patients who come into the hospital with COVID -- that's still happening -- as well as how we evaluate, as we weigh the Johnson & Johnson vaccine and the risk of complications from COVID. So thank you for taking the time.

ALEX SPYROPOULOS: Thank you for inviting me.

JOHN WHYTE: If you have questions about COVID, drop us a line. You can email me drjohn@webmd.net. Thanks for watching.

This interview originally appeared on WebMD on November 17, 2021

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