Enoxaparin Is Associated With Lower Rates of Thrombosis, Kidney Injury, and Mortality Than Unfractionated Heparin in Hospitalized COVID Patients

Abstract

Although anticoagulants such as unfractionated heparin and low molecular weight heparin (LMWH, e.g. enoxaparin) are both being used for therapeutic mitigation of COVID associated coagulopathy (CAC), differences in their clinical outcomes remain to be investigated. Here, we employ automated neural networks supplemented with expert curation (‘augmented curation’) for retrospectively analyzing the complete electronic health records (EHRs) of 671 hospitalized COVID-19 patients administered either enoxaparin or unfractionated heparin, but not both. We find that COVID-19 patients administered unfractionated heparin but not enoxaparin have higher rates of mortality (risk ratio: 2.6; 95% C.I.: [1.2-5.4]; p-value: 0.02; BH adjusted p-value: 0.09), thrombotic events (risk ratio: 5.7, 95% C.I.: [2.1, 33.9], p-value: 0.024), acute kidney injury (risk ratio: 5.5; 95% C.I.: [1.2-17.7]; p-value: 0.02; BH adjusted p-value: 0.10), and bacterial pneumonia (risk ratio undefined; 95% C.I.: [1.0, 292]; p-value:0.02; BH adjusted p-value:0.10), compared to patients administered enoxaparin but not unfractionated heparin. Notably, even after controlling for potential confounding factors such as demographics, comorbidities, admission diagnosis, initial ICU status, and initial level of oxygen support, the above differences between the enoxaparin and unfractionated heparin patient cohorts remain statistically significant. This study emphasizes the need for mechanistically investigating differential modulation of the COVID-associated coagulation cascades by enoxaparin versus unfractionated heparin.Funding Statement: ADB is supported by Grants AI 110173 andhttps://projectreporter.nih.gov/project_info_details.cfm?aid=9696333&icde=49988503&ddparam=&ddvalue=&ddsub=&cr=2&csb=default&cs=ASC&pball=from NIAID, 109593-62-RGRL from Amfar, and the HH Sheikh Khalifa Bin Zayed Al-Nahyan named professorship from Mayo Clinic. Declaration of Interests: The authors from nference have financial interests in the company. ADB is a consultant for Abbvie, is on scientific advisory boards for nference and Zentalis, and is founder and President of Splissen therapeutics. One or more of the investigators associated with this project from the Mayo Clinic and the Mayo Clinic have a Financial Conflict of Interest in technology used in the research. The investigator(s) and Mayo Clinic may stand to gain financially from the successful outcome of the research. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies.Ethics Approval Statement: This research was conducted under IRB 20-003278, “Study of COVID-19 patient characteristics with augmented curation of Electronic Health Records (EHR) to inform strategic and operational decisions”, approved by the Mayo Clinic’s institutional review board (IRB).