Studies published in The New England Journal of Medicine showed that treating moderately ill hospitalised coronavirus disease 2019 (COVID-19) patients with therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. However, the use of this treatment strategy for critically ill COVID-19 patients requiring intensive care did not result in the same outcomes.
To accelerate evidence generation, researchers integrated three platforms evaluating therapeutic-dose anticoagulation with heparin in patients hospitalised with COVID-19 into a single multiplatform, randomised, controlled trial. During the trial period, moderately ill patients were enrolled at 121 sites in 9 countries, whereas critically ill patients were enrolled at 393 sites in 10 countries.
Researchers defined moderately ill patients as those hospitalised for COVID-19 without the requirement for respiratory or cardiovascular organ support, whereas critically ill patients were those hospitalised for COVID-19 requiring intensive care level of support, including respiratory and/or cardiovascular organ support.
The final analysis of trial data included 1,098 critically ill and 2,219 moderately ill patients. For both moderately and critically ill patients, the primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge.
Among 2,219 moderately ill patients, the posterior probability that therapeutic-dose anticoagulation increased organ support–free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). Of the 1,048 patients in the usual-care thromboprophylaxis group, 801 (76.4%) survived until hospital discharge without receipt of organ support during the first 21 days, as compared with 939 of 1,171 patients (80.2%) in the therapeutic-dose anticoagulation group. The adjusted absolute between group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2).
A major thrombotic event or in-hospital death occurred in 94 of 1,180 patients (8.0%) in the therapeutic-dose anticoagulation group and in 104 of 1,046 patients (9.9%) in the thromboprophylaxis group. The analysis of the end point incorporating the occurrence of deep venous thrombosis had similar results. Meanwhile, major bleeding occurred in 22 of 1,180 patients (1.9%) in the therapeutic-dose anticoagulation group and in 9 of 1,047 (0.9%) in the usual-care thromboprophylaxis group. Further, fatal bleeding occurred in 3 patients in the anticoagulation group and in 1 patient in the thromboprophylaxis group. There were no episodes of intracranial bleeding or confirmed heparin-induced thrombocytopenia.
“On the basis of these findings, for every 1,000 hospitalised patients with moderate disease, an initial strategy of therapeutic-dose anticoagulation, as compared with usual-care thromboprophylaxis, would be anticipated to result in the survival of 40 additional patients until hospital discharge without organ support at the expense of 7 additional major bleeding events,” wrote Patrick R Lawler, MD, Peter Munk Cardiac Centre at University Health Network, Toronto, Canada, and colleagues, for the study involving moderately ill patients.
“In contrast to the benefit we found in noncritically ill patients, a parallel analysis from the same multiplatform trial showed that empirical therapeutic-dose anticoagulation was not beneficial in critically ill patients … In a separate randomised trial involving critically ill patients with COVID-19, intermediate-dose heparin was likewise not beneficial,” the authors noted. “It is possible that therapeutic-dose heparin cannot influence the cascade of inflammation, thrombosis, and organ injury in patients with advanced disease. It is also possible that differences in the patient populations, aside from illness severity, may have contributed to these findings.”
Among 1,098 critically ill patients, the median value for organ support–free days was 1 (interquartile range [IQR], −1 to 16) among the 534 patients assigned to therapeutic-dose anticoagulation and was 4 (IQR, −1 to 16) among the 564 patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility, 99.9%). On the other hand, the percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11; posterior probability of inferiority, 89.2%).
Although fewer patients had major thrombotic events in the group assigned to receive therapeutic-dose anticoagulation than in the group assigned to receive usual-care pharmacologic thromboprophylaxis (6.4% vs. 10.4%), the researchers observed that the incidence of the secondary efficacy outcome of major thrombotic events or death was similar in the two groups (40.1% and 41.1%, respectively; median adjusted odds ratio, 1.04; 95% credible interval, 0.79 to 1.35). An analysis incorporating deep-vein thrombosis showed similar results. Meanwhile, major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis.
“Our results refute the hypothesis that routine therapeutic-dose anticoagulation benefits critically ill patients with COVID-19. This hypothesis was based in part on observational studies that reported an association between therapeutic-dose anticoagulation and improved outcomes,” wrote Ewan C Goligher, MD, University of Toronto, Toronto, Canada, and colleagues, for the study involving critically ill patients.
“The net effect of anticoagulation on clinical outcomes in patients with COVID-19 may depend on the timing of initiation in relation to disease course and may vary with the severity of illness (and the degree of coagulation or inflammation) at the time that therapy is commenced,” the authors explained. “Despite demonstrable activation of coagulation in multiple organ systems in patients with severe COVID-19, it is possible that initiation of therapeutic-dose anticoagulation after severe COVID-19 has developed may be too late to alter the consequences of established disease processes.”