Anticoagulation Therapy in Patients With Coronavirus Disease 2019

Results From a Multicenter International Prospective Registry (Health Outcome Predictive Evaluation for Corona Virus Disease 2019 (HOPE-COVID19))

Francesco Santoro, MD, PhD; Ivan J. Núñez-Gil, MD, PhD; María C. Viana-Llamas, MD; Charbel Maroun Eid, MD; Rodolfo Romero, MD; Inmaculada Fernández Rozas, MD; Alvaro Aparisi, MD; Victor Manuel Becerra-Muñoz, MD; Marcos García Aguado, MD; Jia Huang, MD; Ludovica Maltese, MD; Enrico Cerrato, MD; Emilio Alfonso-Rodriguez, MD; Alex Fernando Castro Mejía, MD; Francisco Marin, MD; Sergio Raposeiras Roubin, MD; Martino Pepe, MD; Victor H. Moreno Munguia, MD; Gisela Feltes, MD; Jesus Varas Navas, MD; Bernardo Cortese, MD; Luis Buzón, MD; Cristoph Liebetrau, MD; Raquel Ramos-Martinez, MD; Antonio Fernandez-Ortiz, MD; Vicente Estrada, MD; Natale Daniele Brunetti, MD, PhD


Crit Care Med. 2021;49(6):e624-e633. 

In This Article

Materials and Methods

Study Design and Population

We present data from a cohort study of 5,838 patients with COVID-19 infection enrolled in the multicenter international Health Outcome Predictive Evaluation for Corona Virus Disease 2019 (HOPE-COVID19) Registry (, NCT04334291).

The protocol was established through a consortium of physicians from Italy, Spain, Ecuador, and Germany. Patients were enrolled from seven countries (Spain, Italy, Ecuador, Cuba, Germany, China, and Canada).

Detailed information about participating countries and hospitals is reported on website of the Registry. All patients were diagnosed with COVID-19 according to World Health Organization (WHO) interim guidance through polymerase chain reaction (PCR) testing.[8] In this analysis, hospital data and patients were included until May 5, 2020.

All patients discharged (deceased or alive) from any hospital center were included in the Registry.

The local ethics committee approved this study and was consistent with Helsinki declaration. All local principal investigators reviewed the draft and checked for the accuracy and veracity of data. A list of participating hospitals, investigators, collaborators, and the protocol are available in the Supplementary Appendix ( and on the website of the project (

Data Extraction

Epidemiological, clinical, and outcome data were manually extracted from electronic medical records and assessed by medical researchers.

The individual components of all definitions of clinical outcomes were recorded separately and checked by at least two persons in each hospital. Patient's data were confidentiality protected by assigning all the data in anonym form and the electronic data were stored and/or filled in an encrypted, password-protected computer/website.

Pharyngeal swab samples were obtained from all patients at admission and tested using real-time reverse transcriptase-PCR assays according to the WHO recommendation. Additionally, patient's data including blood test, coagulation, and biochemical tests and chest radiographs or CT were extracted. Comorbidities were evaluated at admission (hypertension, dyslipidemia, diabetes mellitus, obesity, current smoking, renal insufficiency, lung disease, cardiac disease, cerebrovascular disease, connective tissue disease, liver disease, cancer disease, and others). All drugs at admission and previous to hospitalization were recorded. All decisions and clinical procedures were performed by the attending physician team independently of this study following the local regular practice and protocols.

Anticoagulation Therapy

Patients were included in the anticoagulation group if they were treated during hospitalization with systemic or prophylactic anticoagulation including oral, subcutaneous, or IV forms. Patients without information on anticoagulation (n = 31) were excluded from analysis.

Major bleeding was defined as 1) values of hemoglobin less than 7 g/dL with a drop of at least 2 g/L within 24 hours and any RBC transfusion, 2) at least two units of RBC transfusion within 48 hours, or 3) a diagnosis code for major bleeding including intracranial hemorrhage, hematemesis, melena, peptic ulcer with hemorrhage, colon, rectal, or anal hemorrhage, hematuria, ocular hemorrhage, and acute hemorrhagic gastritis.

Outcome and Endpoint

We considered as primary endpoint all-cause mortality during hospitalization. Other events were recorded as secondary endpoints, such as invasive mechanical ventilation, noninvasive mechanical ventilation, prone, respiratory insufficiency, heart failure, renal failure, upper respiratory tract involvement, pneumonia, sepsis, systemic inflammatory response syndrome, clinically relevant bleeding, hemoptysis, and embolic events. Events were allocated following local researchers' criteria upon HOPE COVID-19 registry definitions.

Statistical Analysis

Data are presented as means ± SD for continuous variables with a normal distribution and as frequency (%) for categorical variables. The Kolmogorov-Smirnov test was used to assess normal distribution. Student t test and the Mann-Whitney U test were used to compare continuous variables with normal and non-normal distributions, respectively. The chi-square test or Fisher exact test was used to compare categorical variables. Survival was plotted on Kaplan-Meier curves and assessed with log-rank test. Relative risk with 95% CIs was calculated. Factors with p value of less than 0.05 on univariate analysis were entered into Cox' multivariable regression analysis to define independent risk factors for the outcome.

Statistical analysis was performed with SPSS Statistics 24.0 (IBM, Armonk, NY). A p value of less than 0.05 was considered as statistically significant, all tests were two-sided.