Matthew Neal, MD, Trauma Surgeon, University of Pittsburgh School of Medicine, talks about blood thinners and their effect on COVID.
I want you to if you wouldn’t mind describing for our viewers the ACTIV-4A trial and what you and your colleagues are looking at?
NEAL: Throughout the COVID-19 pandemic we recognized that this disease seems to be uniquely characterized by the formation of blood clots. And those blood clots are both clots that occur in large vessels with things like stroke and deep vein thrombosis but also small vessel clots that we think might contribute to some of the organ failure that we see in COVID patients, in particular in the lungs. And so, with the early recognition of this problem of blood clotting we sought to assess whether using a therapy of anti-coagulation or blood thinning would be beneficial to patients. The ACTIV-4A trial looked at whether the blood thinning medication Heparin was beneficial in reducing clotting complications in COVID-19 patients.
Why Heparin in particular?
NEAL: Heparin was an important choice for the medication for this trial. Heparin is well known as a blood thinner, but Heparin also has anti-inflammatory properties. And it seems to reduce inflammation. And, in addition to noticing blood clots throughout the system and COVID patients, we know that COVID is characterized by markers of inflammation that are very high, more than other respiratory or viral diseases. We thought that perhaps the combined effect of a blood thinner and an anti-inflammatory strategy may be beneficial.
Can you tell me a little bit about the trial? You looked at two patient populations?
NEAL: Right. So, we were interested in understanding the specific patient population that would benefit from Heparin. And we looked at both patients who were in the hospital but did not require an intensive care level of care and also patients who were in the intensive care unit who were critically ill. And I think, really, the important underlying question was the timing of intervention. We needed to know when to start the therapy in addition to whether the therapy was going to be beneficial.
And what did you find?
NEAL: What we found, first of all, was that utilizing Heparin was incredibly safe and that was important. We had concerns at the outset in a patient population that’s very sick that utilizing a blood thinner could result in bleeding complications. And we were pleased to learn that the medication was, actually, very safe to utilize. What we found is, actually, sort of the opposite of what we thought we would find when we started out. We saw that the highest rates of blood clots were in the sickest patients, those in the intensive care unit. And we thought that from the outset those may be the patients who benefited the most from Heparin. But in fact, what we found was it was the patients who weren’t quite sick enough yet to end up in the intensive care unit. They were sick enough to be in the hospital but didn’t require organ support and didn’t require intensive care medicine. Those were the patients that actually benefited from Heparin. And we don’t exactly know why that group, as opposed to the sickest group, benefited. But one potential reason may be that actually starting the medication before one becomes critically ill maybe the most beneficial time.
How much better did they do on Heparin than if there had been no intervention? Is there a way to measure that?
NEAL: Yeah. It’s challenging to quantify because of the way the study was done. But what we do know is that patients who were moderately ill, so sick enough to be in the hospital but not in the ICU, when started on Heparin were less likely to require ICU level of care and less likely to die.
How important are these findings? What is the next step when you have findings like this?
NEAL: I think the studies are incredibly important because the standard of care for COVID has been evolving on a daily and weekly basis since the pandemic started. And this has been a question from the outset. And I can tell you that, you know, we had the experience early in the trial of surveying what clinicians were doing all over the world and it was incredibly variable. The practice was the furthest thing from standardized. And people were doing what they thought was the very best thing they could do for their patients. But there was no guideline or recommendation, yet everybody recognized that we probably should be doing something about blood clotting. So, given the number of patients affected across the globe from COVID-19, having a standardization of practice is incredibly important. But, you know, I would add that, although we definitely found a benefit to patients who were moderately ill, the benefit was modest. And there is absolutely room to improve. And so ACTIV-4 is continuing as a trial. And now that we have established that utilizing Heparin should be standard care, utilizing higher doses of Heparin in moderately ill patients and preventative doses of Heparin in severely ill patients, we want to know what to add to that in order to improve outcomes. And we’re actually completing an additional arm of the trial now where we are targeting a different type of blood thinning medication, in this case a medication that targets platelets, which are an important part of the blood clotting system, to know whether adding an anti-platelet agent to the standard care of a blood thinner improves outcomes even more than what we achieved in the first arm of ACTIV-4.
Is the standard of care here at UPMC and other UPMC facilities, is it the standard of care in other US facilities? Do you know?
NEAL: That’s a great question. With a rapidly evolving problem like COVID the guidelines need to catch up. And when we ask what standard of care means, standard of care can be defined by societies, associations, recommendations and individual hospitals. And, as a result of our trial findings, we’ve made a recommendation throughout the UPMC system to adopt the findings of ACTIV-4 and to utilize therapeutic or high dose anti-coagulation in hospitalized patients who don’t require ICU care.
Do you know if there are any hospitals across the country that are also taking a look at your findings and considering adopting them?
NEAL: Yeah. We’ve heard from many hospitals that they have adopted the findings into their hospital protocols. But we’ve also heard from others who have not. As recently as today one of the other investigators in the trial expressed frustration that their hospital has not yet adopted that. And it is a process and evolution. I think people look at the data very critically. There are other trials in this space, I think, that need to be analyzed. And the standard of care for COVID is really rapidly evolving. But, you know, we’re delighted to be on the front line of that.
Is there anything I didn’t ask you that you want to make sure people know?
NEAL: I think it’s critical to recognize that, although the ACTIV-4 trial, which was funded by the National Institutes of Health, and was an international trial made key contributions to this, that the actual results from the trial came at an incredible pace only as result of a partnership with two other platforms, the REMAP-CAP and ATTACC platforms. This idea of combining three different platform trials into one entity to achieve results with this level of efficiency and speed is completely unprecedented. This was what was necessary for pandemic response. And these platforms came together to achieve that. And that’s the reason we got answers as quickly as we did.
Interview conducted by Ivanhoe Broadcast News.
END OF INTERVIEW
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