Previous studies investigating the role of anticoagulation among patients with COVID-19 have had varied results, but none have reported harm.^{11,12,25–32} Variations in reported associations likely derive from different exposure definitions of anticoagulation, both form and dose. Additionally, different patient populations (e.g., disease-specific cohorts), comparator groups, and inclusion/exclusion criteria were used. One of the largest observational studies to date by Nadkarni et al reported that both prophylactic and therapeutic anticoagulation were associated with a reduction in inpatient mortality by up to 55% compared to those not receiving anticoagulation across five New York City hospitals.¹¹ However, the study allowed patients to switch exposure groups during follow-up without comprehensively accounting for time-updated confounding by indication that may have impacted results.

Our study was designed to emulate a hypothetical clinical trial in which we excluded prevalent users of anticoagulation, balanced covariate distribution at hospital admission (analogous to randomization) and ascertained exposure within 24 hours of admission. We conducted an intention-to-treat analysis since the data required to account for time-updated exposures and confounders (e.g., marginal structural modeling) may not be available within acute hospitalizations. For example, many hospital systems report all diagnoses that occur during a given hospitalization at discharge. Therefore, we could not determine if initiation of prophylactic anticoagulation later in hospitalization confers benefit. There are multiple clinical trials in progress to determine dosing and timing for anticoagulation during the clinical course of COVID-19.¹⁰ Until clinical trial data are available, our results provide strong evidence for the use of prophylactic anticoagulation as initial therapy for COVID-19 patients upon hospital admission.

Thromboembolic events in the context of COVID-19 are strongly associated with mortality.^{3,25,31,33,34} The etiology of heightened thrombosis remains unclear, although proposed mechanisms have included systemic inflammation, endothelialitis, and activation of the complement system.^35–37 Increases in a variety of inflammatory pathways, including bradykinin, interleukin-6, C-reactive protein, and growth differentiation factor 15, have been described in COVID-19.^8,9,38–47 Further, heparin has been shown to block SARS-CoV-2 viral spike protein binding in experimental studies.^48–50 We postulate that the combination of heparin’s known antithrombotic and anti-inflammatory effects,^6,7 in addition to viral infectivity attenuation may, at least in part, explain the observed benefit associated with prophylactic anticoagulation.