Optimal Anticoagulant Dosing in Patients with COVID-19, a Retrospective Review
Authors: Carrillo Alessandra , Punatar Shil , Pavaluri Sushma , Jentink Madeline , Patel Dixita , Braun Joseph , Todorova Tsvetelina , Safarpour Damoun , Farooqui Marwah W , Ghouse Masood , Srinivasan Krishnan 
Published: November 2021

Abstract
Background
Hospitalized patients with coronavirus disease 2019 (COVID-19) infection have higher rates of venous thromboembolism (VTE).Higher mortality rates have been reported in severe cases of COVID-19 including those who have elevated D-dimer levels and have thromboembolic phenomena.
Objective
The objective of this retrospective and observational study was to ascertain which type and dosages of anticoagulation provide a mortality benefit and decrease the risk of developing VTE.
Methods
We evaluated the risk factors for VTEs in patients with a confirmed polymerase chain reaction test positive for COVID-19 who were admitted to our facility from April 1 to July 1, 2020. In addition, we performed a logistic regression to examine the relationship between mortality and intensive care unit (ICU) admission, specific risk factors outlined in the study, D-dimer, ferritin, prothrombin time (PT) and international normalized ratio (INR). Patients with a history of VTE, those already on anticoagulation (AC) prior to hospitalization, and patients on comfort care were excluded from study.
Results
There were originally 331 patients in the data set. Of those, 111 patients were excluded based on exclusion criteria and 4 additional patients were removed as they were the only individual patients in their specific AC covariant group. The analysis was performed on the remaining 216 patients. We divided the AC medications administered to the patients into five separate covariates: 1. enoxaparin 40 mg subcutaneous (sq) daily, 2. enoxaparin 40 mg sq every 12 hours (q12h), 3. heparin 5000 mg sq q12h, 4. heparin 5000 mg sq every 8 hours (q8h), 5. Patients taking multiple AC or deep venous thrombosis (DVT) prophylaxis medications. 6. No AC and examined them via logistic regression for mortality at 28 days and 60 days (Table 1). Patients in enoxaparin 40 mg daily group had statistically significant lower 28 day mortality. There was no statistically significant relationship between the use of enoxaparin 40 mg q12h and 28 day mortality rate. Patients in both heparin groups did not have significantly lower 28 day mortality rates. Patients in groups 5 & 6 had significantly higher 28 day mortality rates (Table 1). It is important to note that 33 patients underwent a pulmonary computed tomography angiography due to concern for pulmonary embolism and 38 patients underwent an ultrasound of their lower extremities to rule out the development of DVT.
For patients with additional risk factors defined as chronic kidney disease, chronic obstructive pulmonary disease, organ transplant recipient, obesity (BMI &gt; 30), cardiac disease (heart failure, coronary artery disease or cardiomyopathy), sickle cell disease, diabetes mellitus and smoking history, the odds of death at 28 days increased by a factor of 1.71, at 60 days by a factor of 1.63 and being admitted to the ICU by a factor of 1.41. Patients with 3-5 risk factors are 2.48 times more likely to be admitted to the ICU than patients with 0-2 risk factors. Patients with 4 or 5 risk factors are 3.56 times more likely to be admitted to the ICU than patients with 0-3 risk factors (Table 2). Predictably, patients that were admitted to the ICU had a significantly increased rate of mortality compared to those who were not (Table 3).
Per our analysis, there was no relationship between PT or INR and mortality. At 28 days and 2 months, the D-dimer &gt; 4000 was indicative of a higher odds of death versus patients with a D-dimer &lt; 4000. An increased ferritin was also indicative of a higher mortality rate (Table 4).
Conclusion
Patients receiving enoxaparin 40 mg daily benefited more than any other AC regimen with respect to the development of VTE at both 28 days and 2 months. Increasing the dosing to twice daily did not decrease mortality. Additionally, patients receiving heparin did not have a decreased mortality. It is important to note that there was no standard protocol used to determine which patients received daily or twice daily dosing. The type and dose of AC was determined based on the clinical judgment of intensivists in each case. It is also possible that patients with severe COVID-19 infection were more likely to be given twice daily dosing which could account for the lack of mortality benefit with more frequent dosing. We did not report bleeding rates in AC groups in our study and this can be a possible reason for no mortality benefit among higher dose AC groups.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.