W. Keith Hoots, M.D., director of the Division of Blood Disorders and Resources (DBDR) at the National Heart, Lung, and Blood Institute (NHLBI), shares insight into how treatments that break up and prevent blood clots are helping adults recover from COVID-19.
These treatment strategies are part of ongoing research supported by the National Institutes of Health’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) network.
What is the goal of ACTIV-4 Antithrombotics, an NHLBI response to COVID-19?
The original goal of ACTIV-4 research was to see if treatments that prevent blood from clotting could help patients recover from COVID-19. Blood clots can increase the risk for heart attack or stroke, and researchers wanted to see how to help patients reduce those kinds of risks, which often require intensive care treatment and could even lead to premature death. The researchers continue to study how the timing and amount of these medications impact recovery at various points of infection.
What studies are part of the ACTIV-4 network?
There are four arms of ACTIV-4 research.
The first, the ACTIV-4 inpatient protocol, assesses how anti-clotting medications and blood thinners help patients in the hospital, which was the original goal of the study.
The second, the ACTIV-4 outpatient protocol, assesses how these therapies could help patients with milder cases recovering outside of the hospital. Researchers found no benefit from anti-clotting medications in that arm, so the trial was stopped early.
The third, the ACTIV-4 convalescent protocol, assesses if and how these anti-clotting therapies could support the long-term recovery of patients who have left the hospital.
The fourth, the ACTIV-4 host tissue protocol, consists of “blockade studies” that evaluate how drugs might prevent the virus from entering cells and setting off extreme immune responses, such as severe blood clotting.
ACTIV-4 is an adaptive research trial. What does this mean?
All clinical trials help researchers answer questions. However, instead of starting a new trial each time a question is answered, an adaptive trial builds on that knowledge. You can take what you’ve learned after you asked the first question and use that as the basis of standard of care treatment. Every question after that becomes a new arm of the adaptive trial.
Why have adaptive trials been important to use during the pandemic?
In addition to quickly answering questions, the adaptive trials pool and maximize resources. The number of sites required for a pandemic trial, along with the start-up investment, is huge. Starting and stopping trials is expensive. The adaptive trial design starts with a foundational knowledge of therapeutics and builds or expands on those outcomes.
What have ACTIV trials shown so far?
As we established the ACTIV adaptive trials, it became clear that COVID-19 led to severe inflammation that caused clotting in the lining of blood vessels for some patients. With the first ACTIV-4 hospital inpatient studies, we found blood thinners and anti-clotting treatments could help offset this effect.
Patients in intensive care who required breathing assistance and other types of support responded better to a lower dose of heparin, a blood thinner, paired with anti-clotting medications. However, a full dose of the blood thinner proved more effective for patients in the hospital who did not require intensive care. Not surprisingly, part of the reason for the difference in response to dosing was bleeding. Patients in the intensive care unit group experienced more bleeding and related complications – which offset some of the potential benefits of a higher dose of heparin.
We also found no benefits in using anti-clotting medications or blood thinners for patients with moderate COVID-19 cases who recovered at home. This was the ACTIV-4 “pre-hospital” trial. Fortunately, the number of patients with milder COVID-19 cases who required hospitalization after infection was low in this trial – regardless of which one of four treatments they were randomly assigned to receive: aspirin, a lower or higher dose of blood thinners, or no treatment at all. Since we found no difference in adverse outcomes among these groups, we stopped the trial early.
What research is underway right now?
Now that we’ve assessed how anti-clotting medications and blood thinners help people recover from COVID-19 in the hospital or at home, we’re evaluating how these therapies may help patients after they leave the hospital. These are the ACTIV-4 convalescent studies. We’re also seeing if these treatments can support patients who experience long-term or lingering effects of COVID-19.
What about preventing infections and severe inflammation?
Through the ACTIV-4 host tissue trials, researchers are trying to determine if a few different drugs can alter how a person’s immune system responds to the coronavirus. Specifically, these studies are looking at how treatment can interfere with the virus’s ability to attach to angiotensin-converting enzyme (ACE2) receptors, a kind of cellular doorway for infection. Will these treatments lock that door or put up barricades that prevent extreme inflammation, including clotting? That’s what we aim to find out. Another anti-inflammatory agent called fostamatinib, which has been used to alter extreme immune responses in immune thrombocytopenia, a rare bleeding disorder, is also part of that “blockade study.”
What results are you looking forward to learning about?
Throughout ACTIV-4 research, we’ve studied how therapies help patients in the hospital, before they get to the hospital, after they leave the hospital, and now before infection. The post-hospital and blockade studies are ongoing, but we haven’t stopped looking at how to advance therapies for patients who require hospital care.
One ACTIV-4 inpatient study, which we’re calling version 1.1, assesses how inhibiting the earliest stages of inflammation may alter severe COVID-19 outcomes. So far, we found that adding a P2Y12 antiplatelet drug to standard of care [blood thinners and heparin] didn’t impact patients at the hospital who were not in intensive care. However, we’re now trying to find out if this treatment strategy may help patients recover faster in the intensive care unit.
Additional research is exploring how repurposing two anti-inflammatory drugs may also help intensive care patients. One drug, crizanlizumab, is currently used to reduce inflammation in patients with sickle cell disease. Another is an anti-inflammatory treatment used for kidney and metabolic conditions. Prior research has shown these drugs are safe. Now, through an ACTIV-4 inpatient study we’re calling version 1.2, we’re seeing if adding these therapies to standard of care is effective.
What can the public learn from adaptive trials?
You just have to go step by step. And we’re still learning. What I’ve explained so far is what we know at this point in time. With any research, if you find a benefit, fantastic. But if you don’t find a benefit, it saves you from having to go back in that direction in future trials. So far, we’ve seen it all. We’ve had positive benefits. We’ve had no benefits. We’ve had mild or neutral benefits. With these new ACTIV-4 arms coming on, we’re hopefully going to learn something about the biology of this particular virus and the way to interfere with its ability to cause disease.
Where can people learn more about ACTIV-4 research?
To learn about the ACTIV-4 clinical research trials, visit https://www.nih.gov/research-training/medical-research-initiatives/activ/covid-19-therapeutics-prioritized-testing-clinical-trials#activ4.
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