Anticoagulation, Bleeding, Mortality, and Pathology in Hospitalized Patients With COVID-19

Abstract

Background: Thromboembolic disease is common in coronavirus disease-2019 (COVID-19). There is limited evidence on the association of in-hospital anticoagulation (AC) with outcomes and postmortem findings.

Objectives: The purpose of this study was to examine association of AC with in-hospital outcomes and describe thromboembolic findings on autopsies.

Methods: This retrospective analysis examined the association of AC with mortality, intubation, and major bleeding. Subanalyses were also conducted on the association of therapeutic versus prophylactic AC initiated ≤48 h from admission. Thromboembolic disease was contextualized by premortem AC among consecutive autopsies.

Results: Among 4,389 patients, median age was 65 years with 44% women. Compared with no AC (n = 1,530; 34.9%), therapeutic AC (n = 900; 20.5%) and prophylactic AC (n = 1,959; 44.6%) were associated with lower in-hospital mortality (adjusted hazard ratio [aHR]: 0.53; 95% confidence interval [CI]: 0.45 to 0.62 and aHR: 0.50; 95% CI: 0.45 to 0.57, respectively), and intubation (aHR: 0.69; 95% CI: 0.51 to 0.94 and aHR: 0.72; 95% CI: 0.58 to 0.89, respectively). When initiated ≤48 h from admission, there was no statistically significant difference between therapeutic (n = 766) versus prophylactic AC (n = 1,860) (aHR: 0.86; 95% CI: 0.73 to 1.02; p = 0.08). Overall, 89 patients (2%) had major bleeding adjudicated by clinician review, with 27 of 900 (3.0%) on therapeutic, 33 of 1,959 (1.7%) on prophylactic, and 29 of 1,530 (1.9%) on no AC. Of 26 autopsies, 11 (42%) had thromboembolic disease not clinically suspected and 3 of 11 (27%) were on therapeutic AC.

Conclusions: AC was associated with lower mortality and intubation among hospitalized COVID-19 patients. Compared with prophylactic AC, therapeutic AC was associated with lower mortality, although not statistically significant. Autopsies revealed frequent thromboembolic disease. These data may inform trials to determine optimal AC regimens.

Keywords: COVID-19; anticoagulation; intubation; mortality.

Graphical abstract

Figure 1

Association of Prophylactic/Therapeutic Versus No Anticoagulation for In-Hospital Mortality and Intubation Stabilized weight-adjusted cumulative incidence curves for the effect of anticoagulation on (A) in-hospital mortality with discharge as a competing risk and (B) intubation with death and discharge as competing risks. The estimates are adjusted for the inverse probability of treatment weighting (IPTW) using propensity scores. Hazard ratio (HR) and 95% confidence interval (CI) are based on stabilized IPTW Fine and Gray’s subdistribution hazard models with robust variance and (A) discharge and (B) death and discharge as competing events. The multivariable model includes therapeutic and prophylactic anticoagulation as time-dependent variables and controls for the effect of time-varying intubation status and respiratory rate and oxygen saturation at admission.

Figure 2

Association of Prophylactic Versus Therapeutic Anticoagulation Started Within 48 h of Hospital Admission on In-Hospital Mortality and Intubation Stabilized weight adjusted cumulative incidence curves comparing the effect of therapeutic versus prophylactic anticoagulation (within 48 h of hospital admission) on (A) in-hospital mortality with discharge as a competing risk and (B) intubation with deaths and discharge as competing risks. The estimates are adjusted for the IPTW using propensity scores. HR and 95% CI are based on stabilized IPTW Fine and Gray’s sub-distribution hazard models with robust variance and (A) discharge and (B) death and discharge as competing events. The multivariable model includes therapeutic and prophylactic anticoagulation as time-dependent variables and controls for the effect of time-varying intubation status. Abbreviations as in Figure 1.

Figure 3

Thromboembolic Disease in Autopsy Specimens From 26 Consecutive Autopsies (A) Pulmonary embolus with lines of Zahn and adherence to the pulmonary vasculature (hematoxylin and eosin, 0.5×). (B) Pulmonary embolus near an intraparenchymal pulmonary lymph node, with lines of Zahn and adherence to the pulmonary vasculature (hematoxylin and eosin, whole slide image). (C) Sequential gross sections of the right frontal lobe of the brain with peripheral infarcts (arrows) and surrounding hemorrhage (ruler shows dimensions in centimeters). (D) Microthrombus in an intraparenchymal brain vessel (hematoxylin and eosin, 20×). (E) Microthrombus within the myocardium with lines of Zahn and adherence to the vascular wall (hematoxylin and eosin, 4×). (F) Microthrombus in a portal venule in the liver (hematoxylin and eosin, 20×).

Central Illustration

In-Hospital Anticoagulation and Outcomes in Coronavirus Disease-2019 Thromboembolic disease is a complication of coronavirus disease-2019 (COVID-19). Prophylactic and therapeutic anticoagulation are associated with better outcomes in hospitalized patients with COVID-19. Randomized controlled trials evaluating different anticoagulation regimens in COVID-19 are needed. CI = confidence interval; DOAC = direct oral anticoagulant; HR = hazard ratio; LMWH = low molecular weight heparin.