Giving moderately ill, hospitalized patients with COVID-19 a full dose of a blood thinner improved their chances of leaving the hospital without needing mechanical ventilation. But this strategy did not yield the same results for patients with COVID-19 who were critically ill and needed intensive care–level support at the time of enrollment.

These are the findings of two new studies published online August 4 in The New England Journal of Medicine. The studies of moderately ill and critically ill patients incorporated data from three platform trials as part of a global collaboration to identify possible treatments during the height of the pandemic. The trials are Accelerating COVID-19 Therapeutic Interventions and Vaccines-4 (ACTIV-4a): A Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic Strategies in Hospitalized Adults with COVID-19; Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC); and Randomized, Embedded, Multi-Factorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) Therapeutic Anticoagulation.

Led by researchers from NYU Grossman School of Medicine, the University of Pittsburgh, and global collaborators, ACTIV-4a was launched after researchers observed that patients that died from COVID-19 had blood clots throughout their bodies, including in their smallest blood vessels. Doctors saw antithrombotics—also known as blood thinners or anticoagulants—as potential treatment because they reduce the risk of clotting. But the field did not know whether a full therapeutic dose that is used to treat blood clots or a low dose typically used to prevent blood clots would be most effective.

“Early on in the pandemic we observed substantial prevalence of clotting in hospitalized COVID-19 patients that caused severe complications,” says Jeffrey S. Berger MD, ACTIV-4a co-principal investigator, co-first author of the study of moderately ill patients, associate professor of medicine and surgery, and director of the Center for the Prevention of Cardiovascular Disease at NYU Langone Health. “It is remarkable to lead a clinical trial that proves early intervention targeting clotting can improve outcomes and avoid many complications associated with COVID-19.”

As part of the research effort, the lead researchers of three platform trials synchronized their study protocols to study the effects of using full and low doses of the anticoagulant heparin in patients hospitalized with COVID-19. Researchers grouped the patients according to whether they had severe or moderate COVID-19 and by their levels of D-dimer, a blood protein that may indicate clotting.

Moderately ill patients hospitalized with COVID-19 were defined as those who did not receive “organ support,” including high-dose oxygen therapy, mechanical ventilation, life support, medicines that increase blood pressure, or medicines that change the force of the heart’s contraction. Patients hospitalized with COVID-19 who did require such support were defined as severe or critically ill.

In April 2020, the research teams started randomly assigning half of their patients hospitalized with COVID-19 to receive either a low or full dose of heparin for up to 14 days after enrollment. By December 2020, oversight boards stopped enrollment of critically ill patients in the trial when interim results showed that full-dose anticoagulation did not reduce the need for organ support, and may cause harm, in severe and critically ill patients. One month later, oversight boards also stopped enrollment of moderately ill patients in the trial when interim results indicated that full doses of blood thinners likely did offer a benefit. The trial enrolled 1,098 critically ill and 2,219 moderately ill patients, and researchers measured how long patients were free of organ support, up to 21 days after enrollment in both cohorts.

Among moderately ill patients, the study authors found that there was a 99 percent chance that full-dose heparin increased the probability of survival to hospital discharge with reduced need for organ support compared to those who received low-dose heparin. However, a small number of patients experienced major bleeding, though this happened infrequently. For critically ill patients, full-dose heparin also decreased the number of major thrombotic events, but it did not result in a greater chance of survival to hospital discharge, or a greater number of days free of organ support than did usual-care pharmacologic thromboprophylaxis, say the authors.

“These results are very exciting and lead us to better understand the impact of applying the right therapies at the right time in the course of this challenging disease,” says ACTIV-4a study chair Judith S. Hochman, MD, the Harold Snyder Family Professor of Cardiology and senior associate dean for clinical sciences at NYU Grossman School of Medicine and a co-corresponding author of the study of moderately ill patients. “Our results will help clinicians utilize known and easily available medical therapies to better treat moderately ill COVID-19 patients,” she says.

ACTIV-4a Antithrombotics Inpatient is conducting further research to test the effects of adding an antiplatelet agent to anticoagulation.

“More work needs to be done to continue to improve outcomes in patients with COVID-19,” says Matthew D. Neal, MD, the Roberta G. Simmons Associate Professor of Surgery at the University of Pittsburgh, co-first author of the study of moderately ill patients and co-senior author of the study of critically ill patients. “Given what we know about the type of blood clots in patients with COVID-19, testing antiplatelet agents is a particularly exciting approach.”

The trials are supported by several funding organizations, including the National Institutes of Health (United States), the Canadian Institutes of Health Research, the National Institute for Health Research (UK), the National Health and Medical Research Council (Australia), and the PREPARE and RECOVER consortia (European Union). The ClinicalTrials.gov identifiers for the two published studies are NCT04505774 and NCT04359277.

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