Blood Thinners Reduce the Need for Mechanical Ventilation in Certain Patients With COVID-19

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

These are the findings of two new studies published online August 4, 2021 in The New England Journal of Medicine. The studies of moderately ill and critically ill patients include data from three platform studies as part of a global collaboration to identify potential treatments during the height of the pandemic. The studies are Accelerating COVID-19 Therapeutic Interventions and Vaccines-4 (ACTIV-4a): a multicenter, adaptive, randomized controlled platform study investigating the safety and efficacy of antithrombotic strategies in hospitalized adults with COVID-19; Antithrombotic Therapy to Improve Complications of COVID-19 (ATTACC); and randomized, embedded, multi-factorial adaptive platform study 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 found that patients who 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 a possible treatment because they reduce the risk of clotting. But the field didn’t know whether a full therapeutic dose used to treat blood clots or a low dose commonly used to prevent blood clots would be most effective.

“Early on in the pandemic, we saw a significant prevalence of clotting in hospitalized COVID-19 patients causing serious complications,” said Jeffrey S. Berger MD, co-principal investigator of ACTIV-4a, co-first author of the study’s moderate sick 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 showing that early intervention targeting clotting can improve outcomes and prevent many complications associated with COVID-19.”

As part of the research effort, the principal investigators of three platform studies 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 based on whether they had severe or moderate COVID-19 and their levels of D-dimer, a blood protein that can 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, medications that raise blood pressure, or medications that increase the strength of the contraction of change the heart . Patients hospitalized with COVID-19 who did require such support were defined as seriously or seriously ill.

In April 2020, the research teams began randomly assigning half of their patients hospitalized with COVID-19 to either low or full-dose heparin for up to 14 days after enrollment. In December 2020, the supervisory boards stopped enrolling critically ill patients in the study when interim results showed that full-dose anticoagulation did not reduce the need for organ support and can cause harm in severely and critically ill patients. A month later, the boards of trustees also stopped enrolling moderately ill patients in the study when interim results indicated full doses of blood thinners likely offered a benefit. The study enrolled 1,098 critically ill and 2,219 moderately ill patients, and researchers measured how long patients were without 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 a full dose of heparin increased the survival rate to hospital discharge with a reduced need for organ support compared to those who received a low dose of heparin. However, a small number of patients experienced serious bleeding, although this was uncommon. For critically ill patients, the full dose of heparin also reduced the number of serious thrombotic events, but did not result in a greater survival rate to hospital discharge, or a greater number of days off from organ support than conventional 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,” said ACTIV-4a study chairperson Judith S. Hochman, MD, de 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 use known and readily available medical therapies to better treat moderately ill COVID-19 patients,” she says.

ACTIV-4a Antithrombotic Inpatient is conducting further research to test the effects of adding a platelet aggregation inhibitor to anticoagulation.

“More 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.”

References:

“Therapeutic anticoagulation with heparin in non-critically ill patients with Covid-19” by The ATTACC, ACTIV-4a and REMAP-CAP Investigators, Aug. 4, 2021, The New England Journal of Medicine.
DOI: 10.1056/NEJMoa2105911

“Therapeutic Anticoagulation With Heparin In Critically Ill Patients With Covid-19” By The REMAP-CAP, ACTIV-4a and ATTACC Investigators, Aug. 4, 2021, The New England Journal of Medicine.
DOI: 10.1056/NEJMoa2103417

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 IDs for the two published studies are NCT04505774 and NCT04359277.