Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19

Abstract

Background Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19. Methods In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. 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. Results The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support–free days was 1 (interquartile range, −1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, −1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%). 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). 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. Conclusions In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis. (REMAP-CAP, ACTIV-4a, and ATTACC ClinicalTrials.gov numbers, NCT02735707 , NCT04505774 , NCT04359277 , and NCT04372589 .)

Methylprednisolone, Venous Thromboembolism, and Association with Heparin to 30 Days Hospital Survival in Severe COVID-19 Pneumonia

“…Most of the patients in the methylprednisolone group require higher oxygen support, and at that time it may be too late. (24,25) Heparin has multiple non-anticoagulant mechanisms that maybe bene cial in COVID-19 earlier in disease course. It is an analogue of haparan sulphate.…”

Methylprednisolone, Venous Thromboembolism, and Association with Heparin to 30 Days in Hospital Survival in Severe COVID-19 Pneumonia

“…At that time, bene ts of therapeutic heparin may be too late. (24,25) Heparin has multiple non-anticoagulant mechanisms that maybe bene cial in COVID-19 earlier in disease course. It is an analogue of haparan sulphate.…”

“…(23) Early therapeutic anticoagulation in critically ill patients have failed to show improved survival. (24,25) Therapeutic anticoagulation was shown to improve survival in patients who are not critically ill or on nasal cannula. (26) Since mortality in COVID-19 ARDS is associated with thrombo-in ammation, there may be a synergistic, dose dependent association with prolonged in hospital survival with methylprednisolone and heparin.…”

Thromboembolism and Bleeding in COVID-19

“…In noncritically ill patients with COVID-19, therapeutic-dose anticoagulation with heparin showed increased survival to hospital discharge and reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis [58]. However, in critically ill patients with COVID-19, therapeutic-dose anticoagulation with heparin did not improve survival or the need for organ support [59]. A separate randomized trial reported that intermediate-dose heparin also was not beneficial in critically ill COVID-19 patients [60].…”