COVID-PACT: What's the Best Anticoagulant Strategy for Critically Ill Patients With COVID-19?

Michelle L. O'Donoghue, MD, MPH; David D. Berg, MD, MPH


September 12, 2022

This transcript has been edited for clarity.

Michelle L. O'Donoghue, MD, MPH: Hi. I'm Dr Michelle O'Donoghue. I'm here at ESC Congress 2022. We are back in person, which is great. There's been terrific science, and one of the late-breaking clinical trials that will be presented will be by my friend and colleague, Dr David Berg, who is an investigator at the TIMI Study Group.

He presented the top-line results of a trial called COVID-PACT, on which I am a co-author. I thought it would be very interesting to talk about this topic in general, as it is still an interesting one.

Welcome, David.

David D. Berg, MD, MPH: Thank you, Michelle. It's a pleasure to be here. Thank you for having me.

O'Donoghue: Let's talk a little bit about the question being asked. Why do we think about clots in the context of COVID-19?

Berg: That's a great question. Relatively early in the pandemic, it was appreciated that patients with COVID-19 have an increased risk of developing blood clots, and that risk is particularly concentrated in patients who require ICU-level care. The exact mechanisms underpinning that increased thrombotic risk are still being sorted out, but there are probably multiple things that contribute to it.

One of the interesting findings has been that the increased thrombotic risk is held constant over time. Even with the introduction of effective therapies and vaccines, if you benchmark the risk for thrombosis in COVID-19 to other viral infections like influenza, that increased dramatic risk has been constant over time.

O'Donoghue: Yeah, it's interesting. It does raise many questions. Has there been any change over time in terms of clotting risk since the start of COVID-19 toward more recent cases?

Berg: That's a great question. There really has not. Some of the early epidemiologic data suggested very high rates, but that came from case reports and case series. Within a few months, when larger epidemiology studies were published, it was appreciated that rates of thrombosis in ICU patients were on the order of 10%-30%. Even with the introduction of effective therapies, that's remained the case.

O'Donoghue: Right. What does the evidence show so far leading up to COVID-PACT? What do we know about different treatments and their effectiveness and safety?

Berg: As you can imagine, there was much enthusiasm to try to understand the effect of antithrombotic therapy in COVID-19 once it was appreciated that there was an increased risk for thrombosis. There have been a number of randomized trials to date that have answered exactly that question or explored that question, looked at increased-intensity anticoagulant therapy or antiplatelet prophylactic strategies. I'd say that the primary results of those studies have been mixed, and in large part because of differences in study designs in the patient populations, and in particular, the study endpoints.

There was one large study, a multiplatform trial, which combined a couple of different trial platforms. There were separate studies in critically ill and non–critically ill patients. The primary endpoint in that study was an organ failure endpoint, so it was number of days alive off organ support through 21 days. Surprisingly, there were different results in the critically ill and non–critically ill patient population.

In non–critically ill patients, the study was stopped for superiority of full-dose anticoagulation. Both of them had the same design of therapeutic dose anticoagulation as compared with standard-dose prophylactic anticoagulation. There was a benefit of full-dose anticoagulation in the non–critically ill patients, but in the critically ill patients that was not seen.

That's led to consensus guidelines based on relatively uncertain evidence to use full-dose anticoagulation in patients who are hospitalized but not in the ICU; but then when they're in the ICU, to use standard-dose prophylaxis.

O'Donoghue: That sets the stage for COVID-PACT. Where did COVID-PACT think it could make an impact, and what patient population did you study?

Berg: COVID-PACT was a two-by-two factorial randomized controlled trial in critically ill patients with COVID-19, so it focused on patients who required ICU-level care. That included patients who were either physically admitted to the ICU or who were receiving ICU-level care outside of the ICU, including advanced respiratory support, vasopressor support, and mechanical circulatory support. They were randomized in a one-to-one allocation ratio to either treatment with full-dose anticoagulation or standard-dose prophylactic anticoagulation.

There was an additional randomization to either clopidogrel or no antiplatelet therapy if patients were not already on antiplatelet therapy. Patients were followed through hospital discharge or day 28 post-randomization. What was different about COVID-PACT compared with the multiplatform trial is that the focus was on thrombotic events. The primary efficacy endpoint was a composite of venous and arterial thrombotic events. That was, I think, the biggest design difference in the studies.

O'Donoghue: It makes sense. If we were thinking about antithrombotic and antiplatelet therapy, I can understand the interest in looking at a clot outcome, specifically. What do the results show?

Berg: The results were very exciting. I'm obviously biased. We enrolled 400 patients for the anticoagulation randomization. When comparing full-dose anticoagulation to standard-dose prophylactic anticoagulation, there was a 44% relative reduction in the risk for the primary efficacy endpoint, which was a composite of venous and arterial thrombotic events. That was a significant reduction. For the comparison of clopidogrel vs no antiplatelet therapy, there was no benefit of clopidogrel.

In addition to looking at thrombotic endpoints, we looked at safety endpoints. As you might expect, with the reduction in thrombotic events, there was an increased risk in bleeding. There were two safety endpoints. The first was fatal or life-threatening bleeding. Fortunately, there were no fatal bleeding events in the study. There were numerically more life-threatening bleeds in patients who were treated with full-dose anticoagulation. That was not a statistically significant difference because there were such few events, but there was a numeric increase.

There was an increase in GUSTO moderate bleeding, which refers to bleeding that results in any transfusion but without hemodynamic instability. It does appear that there is a bit of a tradeoff between a reduction in thrombotic events and an increase in bleeding that is not hemodynamically significant bleeding.

O'Donoghue: I think it's an important contribution. The fact that the antiplatelet therapy had no impact is really notable as well, and perhaps provides some insights into the pathobiology of what's going on at the clot level.

In your practice now, when you're attending in the ICU, do you think that this would change your approach to a critically ill patient with COVID-19? Do you think that you would be treating them across the board with a full-dose anticoagulant or, because of the bleeding concerns, are you going to be more selective? Do you have any advice about any patient groups who perhaps have the better clinical benefit?

Berg: I think that's exactly the question that we're all wondering about, and one that I have grappled with often over the past 2 years. I would say that COVID-PACT supports the efficacy of full-dose anticoagulation for the reduction of thrombotic events. I think it particularly helps because many clinicians have been scratching their heads about how to approach this difference between moderately ill patients and critically ill patients.

Right now, guidelines suggest that these should put patients on full-dose anticoagulation when they're admitted to the hospital. When they get sick, do we stop it? What about that middle-zone patient who's on high-flow nasal cannula? How do we handle that?

I think what we can say now with some confidence is that continuing full-dose anticoagulation or starting full-dose anticoagulation when a patient goes to the ICU is going to reduce their thrombotic risk. It may not affect an organ failure endpoint, but it's going to reduce their thrombotic risk.

I think you raised the obvious question, which is, is that true for everybody? I think we have to be careful about our patient selection and I think it's helpful to think about who was excluded from COVID-PACT. If patients were severely coagulopathic or if they were severely thrombocytopenic, then they didn't end up in a study. If they were on dual antiplatelet therapy, in which case adding full-dose anticoagulation would give them triple therapy, they were excluded. For those patients, I would not use full-dose anticoagulation.

When we looked at patients who did bleed on full-dose anticoagulation, they tended to be quite a bit older than patients who did not bleed. That's a story that we've learned many times. I would be careful using it in elderly patients.

O'Donoghue: That's important. I think that taking a look at clinical trial results in terms of who was excluded and who was included in their patient population is always an important thing to do.

Thank you again for sharing these exciting results. I'm sure we'll see many analyses down the road as you continue to explore the dataset, but congratulations.

Berg: Thank you, Michelle. It's great to be here.

O'Donoghue: Signing off for Medscape, this is Dr Michelle O'Donoghue.

Michelle O'Donoghue is a cardiologist at Brigham and Women's Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she's never strapped on hockey skates.

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