Prophylactic Anticoagulation, Fewer Deaths in Hospitalized COVID-19 Patients

Patients hospitalized with COVID-19 who are treated with prophylactic anticoagulation have a lower risk of death at 30 days when compared with those who don’t receive anticoagulation, according to a new cohort study. Additionally, use of prophylactic anticoagulation was associated with a lower risk of inpatient mortality, as well as less need to start therapeutic anticoagulation, a marker of clinical deterioration.

Importantly, in this cohort of more than 4,200 patients receiving care in the Veterans Affairs (VA) national healthcare system, the use of anticoagulation was not associated with higher risk of major bleeding requiring transfusion.

“We are still awaiting clinical trials to be fully reported,” lead investigator Christopher Rentsch, PhD (London School of Hygiene and Tropical Medicine, England), told TCTMD. “Until then, we think that our findings provide strong, real-world evidence to support guidelines recommending the prophylactic use of anticoagulation as initial therapy upon hospital admission for COVID-19 patients.”

The study appears at a time when the anticoagulation dose, drug, timing, and target group in COVID-19 remains unclear. Studies have repeatedly highlighted an increased risk of thrombotic events in hospitalized patients, neurologic events as initial presentation, multiorgan clotting on autopsy, and the list goes on. Several organizations now recommend prophylactic anticoagulation for hospitalized COVID-19 patients without a contraindication to treatment, but the evidence to date has been confusing, particularly the signal that full-dose anticoagulation may be more beneficial in moderately ill patients but harmful for those already admitted to ICUs.

Several randomized trials, among them FREEDOM COVID-19 and IMPROVE are still ongoing, while the National Institutes of Health-funded ACTIV multiplatform trial (combining the ATTACC, REMAP-CAP, and ACTIV-4a clinical trials) recently halted enrollment after an interim review of data showed that therapeutic anticoagulation compared with prophylactic dosing reduced the need for vital organ support in moderately ill patients with COVID-19. Those results have not yet been published.

An earlier announcement from the ACTIV investigators, however, suggested that full-dose anticoagulation was harmful for critically ill patients requiring ICU-level care.

‘Robust’ Findings

In the present study, Rentsch said their goal was to assess whether prophylactic anticoagulation prescribed at hospital admission was associated with a lower risk of death in a large, nationwide healthcare system. In the VA, they identified 4,297 mostly male patients (mean age 68) admitted to the hospital for COVID-19 between March and July 2020. The study population included 1,940 non-Hispanic Black, 1,603 non-Hispanic white, and 506 Hispanic patients. Of these, 84.4% were started on prophylactic anticoagulation within 24 hours of admission and treated with either subcutaneous heparin-based drugs (30.2%) or enoxaparin (69.1%).

“Interestingly, in terms of all of our acute markers of health, such as labs and vital signs, people who were prescribed prophylactic anticoagulation seemed to be sicker than those who were not prescribed prophylactic anticoagulation,” said Rentsch. “Conversely, when we looked at preexisting health conditions, individuals seemed to have less comorbid conditions if they were prescribed prophylactic anticoagulation than those were not. It was a very interesting patient population.”   

At 30 days, there were 622 deaths. In an inverse probability-weighted analysis, which adjusted for all baseline characteristics, the cumulative incidence of death was 14.3% among those treated with anticoagulation and 18.7% for those untreated. Receiving anticoagulation was associated with a relative 27% lower risk of death at 30 days, a 31% lower risk of inpatient mortality, and a 19% lower incidence of initiating therapeutic anticoagulation, which investigators suggested served as a proxy for deterioration, including thromboembolic events.

Rentsch said their results didn’t surprise them too much, given the multiple societies already recommending use of prophylactic anticoagulation in patients admitted to the hospital with COVID-19. “What we were most surprised about was how robust the results were to a number of sensitivity analyses we performed,” he said. For example, they even saw a benefit when prophylactic anticoagulation was started within 48 hours of admission but noted the evidence of benefit was strongest in patients not admitted to the ICU who received anticoagulation within the first 24 hours.

That fits with the December findings from ACTIV, which came out just 3 days before Rentsch and colleagues turned in their paper’s final revisions to the BMJ. 

Finally, Rentsch emphasized the outstanding quality of data from the VA national database. Even in the National Health Service, which has access to health records from all UK citizens, there are issues with data linkage from different sources that the VA system doesn’t have to deal with because the system is fully integrated. “The quality of research that can be done with VA data is just phenomenal,” he said