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Benefit of full-dose heparin for patients with COVID-19 warrants ‘new standard of care’
Early administration of full-dose heparin slowed the thrombo-inflammatory process and reduced the risk for severe disease and death among moderately ill hospitalized patients with COVID-19, according to a study published in MedRxiv.
The benefits of heparin — a blood thinner that prevents clots and reduces inflammation — for patients with COVID-19 came at the conclusion of the Rapid Response to the COVID-19 Pandemic (RAPID) trial, a multicenter, open-label, randomized trial conducted at 28 sites in six countries.
“In accord with the multiplatform trial that had a similar design, [among] patients hospitalized on the ward with elevated D-dimer (as an indicator of thrombo-inflammation), therapeutic intensity anticoagulation with heparin/low-molecular-weight heparin is effective in reducing progressive disease compared [with] standard of care,” Mary Cushman, MD, MSc, professor of medicine in the hematology and oncology division, professor of pathology and laboratory medicine, and university scholar at Larner College of Medicine at The University of Vermont, told Healio.
Cushman and colleagues recognized hypoxic respiratory failure is the most common cause of clinical deterioration of patients hospitalized for COVID-19. They hypothesized that early initiation of therapeutic heparin could reduce the thrombo-inflammatory process and risk for critical illness or death due to its anticoagulant, anti-inflammatory and potential anti-viral effects.
“Early in the pandemic it became clear that patients hospitalized with COVID-19 had a prominent thrombo-inflammatory drive that related to incidence of respiratory failure, so we believed that heparin might provide a benefit to patients in suppressing this drive,” Cushman said.
The intention-to-treat analysis included 465 patients (mean age, 60 years; 56.8% men; mean BMI, 30.3 kg/m2) admitted to the hospital with laboratory-confirmed SARS-CoV-2 infection and elevated D-dimer levels.
Researchers randomly assigned patients to receive therapeutic full-dose heparin (n = 228) or prophylactic low-dose heparin (n = 237) between May 29, 2020, and April 12, 2021.
A composite of death, invasive mechanical ventilation, noninvasive mechanical ventilation or ICU admission served as the primary outcome. Researchers also investigated major bleeding as a safety outcome.
Results showed the primary composite outcome occurred at 28 days in 16.2% (n = 37) of patients assigned therapeutic heparin and 21.9% (n = 52) assigned prophylactic heparin (OR = 0.69; 95% CI, 0.43-1.1), which did not represent a statistically significant reduction. However, four patients (1.8%) assigned therapeutic heparin died vs. 18 patients (7.6%) assigned prophylactic heparin, equating to a statistically significant decrease in all-cause death of 78% (OR = 0.22; 95% CI, 0.07-0.65).
Researchers also reported a composite of all-cause mortality or any mechanical ventilation among 10.1% (n = 23) of the therapeutic heparin group and 16% (n = 38) of the prophylactic heparin group (OR = 0.59; 95% CI, 0.34-1.02), and major bleeding in two patients (0.9%) with therapeutic heparin and four patients (1.7%) with prophylactic heparin (OR = 0.52, 95% CI, 0.09-2.85).
“Based on the findings, in concert with the multiplatform trial, we believe a new standard of care is warranted,” Cushman said.
Cushman pointed out two other findings from the investigation that surprised researchers.
“[One was] the large effect size that we saw for the secondary outcome of mortality. It is likely there is a true reduction in mortality; when taken in concert with the multiplatform trial, our meta-analysis estimated a reduction of 23% (OR = 0.77; 95% CI, 0.6-0.99),” she said. “[The other was] the low risk [for] major hemorrhage with full-intensity anticoagulation.”
Limitations of the study included the fact it was underpowered and, despite the trial’s open-label design, relevant outcomes were blindly adjudicated by an independent clinical events committee, researchers noted.
“I am anticipating results of ongoing trials of other antithrombotic interventions, such as the current NHLBI-funded ACTIV-4 (Accelerating COVID-19 Therapeutic Interventions and Vaccines 4) trial, evaluating the addition of P2Y12 inhibition to therapeutic-intensity heparin/low-molecular-weight heparin,” said Cushman, who also is an investigator on that trial. “It is especially important to test the combination of treatments, since there is room to move in terms of bleeding side effects as bleeding incidence with therapeutic anticoagulation was low in both the multiplatform trial and RAPID.”
For more information:
Mary Cushman, MD, MSc, can be reached at Larner College of Medicine at The University of Vermont, Division of Hematology and Oncology, Department of Medicine, Colchester Research Facility, 360 South Park Drive, 206D, Colchester, VT 05446; email: mary.cushman@med.uvm.edu.
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