Anticoagulation to Prevent VTE in COVID-19: Interim Analysis
- Therapeutic-dose anticoagulation resulted in fewer days requiring organ support in non-ICU hospitalized patients with COVID-19.
- Therapeutic-dose anticoagulation did not reduce the number of days requiring organ support in critically ill patients with COVID-19.
- Interim results from these three trials have not been adjudicated or peer-reviewed and should be interpreted with appropriate caution.
Does empiric use of treatment-dose anticoagulation improve clinical outcomes in patients hospitalized with coronavirus disease 2019 (COVID-19)?
Three multicenter, randomized, open-label trials (ATTACC [Antithrombotic Therapy to Ameliorate Complications of COVID-19], REMAP-CAP [Randomized Embedded Multifactorial Adaptive Platform for Community-Acquired Pneumonia], and ACTIV-4a [Accelerating COVID-19 Therapeutic Interventions and Vaccines]) were initiated and harmonized with regard to protocol and outcomes measured. Adult patients hospitalized for COVID-19 were enrolled and randomized to receive either therapeutic-dose anticoagulation (low molecular weight heparin or unfractionated heparin) or usual care pharmacologic venous thromboembolism (VTE) prophylaxis. Both anticoagulation doses were administered according to local hospital policy/practice. Therapy was continued for 14 days or hospital discharge (whichever occurred first).
The primary outcome was the number of days the patient was free of any organ support (e.g., mechanical ventilation, vasopressors, extracorporeal membrane oxygenation, or high-flow nasal oxygen administered in the intensive care unit [ICU]). The primary outcome was measured for up to 21 days. Key secondary outcomes included International Society on Thrombosis and Hemostasis (ISTH)-defined major hemorrhage, mortality, intubation, and thrombotic complications. Populations were stratified a priori according to disease severity (severely ill [ICU and/or organ support] vs. moderately ill) and D-dimer level (unknown, <2x upper limit of normal, >2x upper limit of normal). Decision rules to stop for superiority and futility were predefined. Patients who transferred from the medical wards to the ICU during the study period remained on their initially assigned anticoagulation dosing.
A total of 2,895 patients were randomized across the three trials with 2,293 (1,398 moderate and 895 severe) having completed 21 days of follow-up with organ support assessment. A plurality of included patients were ages 60-69 years with more men than women in both the moderate and severely ill cohorts. The critically ill cohort was terminated for futility on December 19, 2020, while the moderately ill cohort was terminated for superiority on January 21, 2021. In the moderately ill cohort, fewer patients required any organ support in the treatment-dose group than in the prophylactic-dose group (~16% vs. ~23%). Death occurred in numerically fewer patients receiving therapeutic anticoagulation in the moderately ill arm (5.7% vs. 7.7%), but numerically more in the severely ill arm (35.3% vs. 32.6%) as compared to prophylactic-dose anticoagulation. Major bleeding occurred in numerically more patients in the therapeutic arm for both illness severity cohorts (1.6% vs. 0.9% for moderately ill, 3.7% vs. 1.8% for severely ill). Thrombotic events occurred in fewer patients receiving therapeutic anticoagulation in both illness severity cohorts (1.9% vs. 3.2% for moderately ill, 6.7% vs. 11.8% for severely ill).
The authors concluded that among moderately ill patients with COVID-19 who are not in the ICU or on organ support, therapeutic-dose anticoagulation was superior to usual VTE chemoprophylaxis with regard to organ support-free days, regardless of presenting D-dimer. They also concluded that for severely ill patients with COVID-19, therapeutic-dose anticoagulation does not improve organ support-free days and may be harmful as compared to thromboprophylaxis.
These three harmonized trials are the first to robustly test the use of treatment-dose versus prophylactic-dose anticoagulation in patients hospitalized with COVID-19. At first glance, the results can be divergent and somewhat confusing. Specifically, it is not yet known why moderately ill patients experienced fewer organ-supported days with treatment-dose anticoagulation, while critically ill patients did not. As expected, the rates of major bleeding were higher in the treatment-dose anticoagulation arm for both the moderate and critically ill cohorts, while rates of thromboembolic events were lower. Outcomes specific to patients who transitioned between the floors and ICU during the study period are not yet known, leaving some uncertainty about how best to manage patients who acutely worsen during their hospital stay.
It should be noted that these results are an interim analysis and many outcomes (e.g., bleeding, thromboembolic events) have not been adjudicated. Furthermore, the results of these three trials have not been peer reviewed. Finally, these three studies compared standard prophylactic-dose versus treatment-dose anticoagulation and did not assess the efficacy or safety of an “intermediate-dose” anticoagulation strategy.
Nonetheless, clinicians and health systems should carefully review these data and re-assess their protocols for VTE prevention strategies among hospitalized patients. It is likely that many moderately ill, but not critically ill, patients would benefit from higher-intensity anticoagulation, as long as bleeding risk is reasonably low. Of note, these studies explored the use of anticoagulation for VTE prevention and did not include patients with confirmed or highly suspected acute VTE for whom treatment-dose anticoagulation is already recommended. Clinicians should carefully monitor for final peer-reviewed publications and confirmatory clinical trials. Further research is needed to best determine how to treat patients who are admitted with critically ill COVID-19 or who acutely worsen during their hospital stay.
Keywords: Anticoagulants, Chemoprevention, Coronavirus, COVID-19, Critical Illness, Extracorporeal Membrane Oxygenation, Fibrinolytic Agents, Hemorrhage, Heparin, Heparin, Low-Molecular-Weight, Intensive Care Units, Intubation, Intratracheal, Length of Stay, Patient Discharge, Post-Exposure Prophylaxis, Primary Prevention, Respiration, Artificial, Thrombosis, Vaccines, Vascular Diseases, Venous Thromboembolism
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