Back in September 2020, TrialSite introduced the National Institute of Health (NIH) ACTIV-4 COVID-19 clinical research program. Coordinated and managed by the National Heart, Lung and Blood Institute (NHLBI), part of the NIH, backed by funding allocation from ACTIV and a number of collaborators, these trials involved over 100 sites around the world in diverse clinical settings—from those who have not been hospitalized, those hospitalized and those discharged after hospitalization. Collectively known as ACTIV-4 Antithrombotics, the sponsors sought to conduct three major trials to offer critical insight to guide the care of patients with COVID-19, especially those who suffer from life-threatening blood clots. What are the results? According to a recent NIH press release, the full dose anticoagulation (blood thinner) treatments, such as affordable heparin, given to moderately ill patients hospitalized for COVID-19 reduced the requirement of vital organ support—such as the need for mechanical ventilation. Importantly, based on the top line results, the investigators observed a trend in possible reduction of mortality—this is still under investigation. With a large number of COVID-19 patients requiring hospitalization, the recent observations are welcome news as this strategy identified by NHLBI could reduce the overload imposed on hospital intensive care units. These most recent findings complement the findings in December that routine use of full-dose anticoagulation when commenced in the ICU in those critically ill with COVIOD-19 isn’t beneficial and may even be more harmful.
Physicians early on as COVID-19 spread around the world noticed increased rates of blood clots and inflammation among COVID-19 patients, which affected multiple organs and led to complications such as lung failure, heart attack and stroke. What wasn’t known at the time: was it safe and effective to administer increasing doses of blood thinners to hospitalized COVID-19 patients?
The program involved three clinical trials platforms across five continents in over 300 hospitals. All came together, thanks to a collaboration involving ACTIV, Operation Warp Speed and several other groups supporting funding as well as NHLBI coordination and management to answer the following question: Can full doses of blood thinners (heparin) help moderately ill hospitalized adults with COVID-19 as compared to the lower heparin dose most frequently administered to prevent blood clots in hospitalized patients? NIH clarified that moderately ill patients for purposes of this program were those individuals not in intensive care and who didn’t require organ support such as mechanical ventilation at trial enrollment.
The three international trials include: the Randomized, Embedded, Multi-factorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAPexternal link) Therapeutic Anticoagulation; Accelerating COVID-19 Therapeutic Interventions and Vaccines-4 (ACTIV-4) Antithrombotics Inpatient; and Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACCexternal link). The trials, which span four continents have the common goal of assessing the benefit of full doses of blood thinners to treat moderately ill or critically ill adults hospitalized for COVID-19, compared to a lower dose often used to prevent blood clots in hospitalized patients. To meet the challenge of this pandemic, investigators worldwide joined forces to answer this question as rapidly as possible. In the United States, the ACTIV-4 trial is being led by a collaborative effort with several universities, including the University of Pittsburgh and New York University, New York City.
The NIH reports that based on the results of over 1,000 moderately ill patients admitted to the hospital, the data thus far reveals that full doses of blood thinners, in addition to being safe were superior to the doses normally given to prevent blood clots in hospitalized patients. This finding is understood in the context of the primary endpoint of the study—that is the need for ventilation or other support interventions.
Principal Investigator Point of View
Jeffrey Berger, MD, co-primary investigator on the SACTIV-4a trial, commented, “This is groundbreaking” and continued, “For hospitalized patients with COVID-19, In think we are going to enter a new era.” While ATTACC principal investigator Ryan Zarychanski, MD, with the University of Manitoba, shared, “This will define a new standard of care for patients with COVID-19 in hospital but not on life support.”
The trials are supported by multiple international funding organizations including Canadian Institutes of Health Research (CAN), the National Institutes of Health’s National Heart, Lung, and Blood Institute (US), the Translational Breast Cancer Research Consortium and the University of Pittsburgh Medical Center Learning While Doing Program (US), the LifeArc Foundation, National Institutes of Health Research (UK), National Health and Medical Research Council (AUS), Minderoo Foundation (AUS), and the PREPARE and RECOVER consortia (EU).
The NIH reports that research questions persist as to how to improve the clinical care of COVID-19 patients. An adaptive protocol, ACTIV-4 was designed to allow different drugs to be introduced and stopped or combined during the study in response to emerging scientific data. The benefit of course is that this method enables the rapid testing of additional agents without compromising safety, while offering the ability to evolve the knowledge in the middle of pandemic conditions. These studies continue but the top line findings represent a breakthrough.
Call to Action: The ACTIV-4 investigators now must work furiously to make the results of the study available so clinicians can make even more informed decisions about treating COVID-19 patients.