Anticoagulation as a therapeutic strategy for hospitalised patients with COVID-19

Abstract

The COVID-19 pandemic has devastated the global community and continues to cause significant morbidity and mortality worldwide. The development of effective vaccines has represented a major step towards reducing transmission and illness severity but significant challenges remain, particularly in regions where vaccine access has been limited. COVID-19 is associated with hypercoagulability and increased risk of thrombosis, with greatest risk among the critically ill. Interestingly, early observational data suggested that anticoagulant therapy might improve clinical outcomes, aside from thrombotic events, in patients with COVID-19. In this review we summarise data generated from three published randomised clinical trials which have sought to determine the effect of therapeutic heparin anticoagulation on efficacy and safety outcomes in hospitalised patients with COVID-19: the multiplatform REMAP-CAP, ACTIV-4a and ATTACC randomised controlled trials and the RAPID trial. In the multiplatform REMAP-CAP, ACTIV-4a and ATTACC randomised controlled trials, therapeutic heparin was not associated with benefit in critically ill patients with COVID-19 compared with usual care (adjusted proportional odds ratio (OR) for increased organ-support free days up to day 21: 0.83; 95% credible interval, 0.67–1.03, posterior probability of futility 99.9%). Conversely, among hospitalised patients without critical illness, therapeutic heparin was associated with an increased probability of organ support-free days alive (adjusted OR, 1.27; 95% credible interval, 1.03–1.58). The RAPID trial also evaluated the effect of therapeutic heparin compared with prophylactic heparin in non-critically ill patients. In this study, therapeutic heparin did not significantly reduce the odds of the primary composite outcome (death, mechanical ventilation or intensive care unit admission) (OR 0.69; 95% confidence interval [CI], 0.43 to 1.10; p = 0.12) but was associated with a significant reduction in all-cause mortality [OR, 0.22 (95%-CI, 0.07 to 0.65)]. Collectively these studies suggest that therapeutic anticoagulation with heparin may reduce the severity of illness and potentially even confer a survival benefit in hospitalised, non-critically ill patients with COVID-19. No benefit for therapeutic anticoagulation with heparin was evident in critically ill patients with COVID-19. Therefore, while the results of additional studies in this evolving field are pending, it is important to approach decisions regarding therapeutic heparin in moderately ill hospitalised patients with COVID-19 in a measured and individualised manner.

Thromboprophylaxis in COVID‐19: Weight and severity adjusted intensified dosing

“…Additionally, patients with a substantial bleeding risk or absolute indication for anticoagulation were excluded in these studies. 38 Our data suggest that striving to monitored weight-adjusted intermediate doses in the critically ill and weight-adjusted prophylactic doses at the wards may represent a good balance between thromboprophylaxis and bleeding. This is further supported by the higher major bleeding rate we report in those patients who received therapeutic-dosed LMWH compared with lower-than-therapeuticdosed LMWH in our population, considering that our intensified but nontherapeutic COVID-19 protocol seems to prevent VTE effectively.…”

“…Additionally, patients with a substantial bleeding risk or absolute indication for anticoagulation were excluded in these studies. 38 …”

“…Furthermore, when looking at D‐dimer subgroups in the multiplatform trial, only the overall cohort showed a significant risk difference and odds ratio confidence interval with “a high probability of superiority” for therapeutic dose anticoagulation; this was not the case in patients with low levels of D‐dimers (less than two times upper limit of normal). Additionally, patients with a substantial bleeding risk or absolute indication for anticoagulation were excluded in these studies 38 …”