Safety profile of enhanced thromboprophylaxis strategies for critically ill COVID-19 patients during the first wave of the pandemic: observational report from 28 European intensive care units
Authors: Lavinio Andrea , Ercole Ari , Battaglini Denise , Magnoni Sandra , Badenes Rafael , Taccone Fabio Silvio , Helbok Raimund , Thomas William , Pelosi Paolo , Robba Chiara ,   collaborators, Innerhofer Nicole , Miori Sara , Librizzi Alberto , Bertuetti Rita , Faria Nicolas Figueiredo , Peluso Lorenzo , Montrucchio Giorgia , Sales Gabriele , Brazzi Luca , Alampi Daniela , Manca Maria Beatrice , Sepe Lilia , Natalini Giuseppe , Bellino Antonio , Bocci Maria Grazia , Mattana Chiara , Corradi Francesco , Forfori Francesco , Cundari Francesco , Bonvecchio Emilio , Busani Zara , Bianchin Andrea , Federico Carla , Santoro Anna , Bilotta Federico , Rajani Giorgio , Lopez Berta Moleon , Aspide Raffaele , Raffaele Merola , Cabrini Luca , Motta Alessandro , Frattini Lara , Godon Alexandre , Bouzat Pierre , Grappa Elena , Bonvecchio Alberto , Innerhofer Nicole , Fries Dietmar , Hernandez Christian Preuss , Thomé Claudius , Klein Sebastian , Joannidis Michael , Pelosi Paolo , Ball Lorenzo , Patroniti Nicolo’ , Brunetti Iole , Bassetti Matteo , Giacobbe Daniele Roberto , Vena Antonio , Valbusa Alberto , Porto Italo , Bona Roberta Della 
Published: April 2021

Abstract
Introduction
Critical illness from SARS-CoV-2 infection (COVID-19) is associated with a high burden of pulmonary embolism (PE) and thromboembolic events despite standard thromboprophylaxis. Available guidance is discordant, ranging from standard care to the use of therapeutic anticoagulation for enhanced thromboprophylaxis (ET). Local ET protocols have been empirically determined and are generally intermediate between standard prophylaxis and full anticoagulation. Concerns have been raised in regard to the potential risk of haemorrhage associated with therapeutic anticoagulation. This report describes the prevalence and safety of ET strategies in European Intensive Care Unit (ICUs) and their association with outcomes during the first wave of the COVID pandemic, with particular focus on haemorrhagic complications and ICU mortality.

Methods
Retrospective, observational, multi-centre study including adult critically ill COVID-19 patients. Anonymised data included demographics, clinical characteristics, thromboprophylaxis and/or anticoagulation treatment. Critical haemorrhage was defined as intracranial haemorrhage or bleeding requiring red blood cells transfusion. Survival was collected at ICU discharge. A multivariable mixed effects generalised linear model analysis matched for the propensity for receiving ET was constructed for both ICU mortality and critical haemorrhage.

Results
A total of 852 (79% male, age 66 [37–85] years) patients were included from 28 ICUs. Median body mass index and ICU length of stay were 27.7 (25.1–30.7) Kg/m2 and 13 (7–22) days, respectively. Thromboembolic events were reported in 146 patients (17.1%), of those 78 (9.2%) were PE. ICU mortality occurred in 335/852 (39.3%) patients. ET was used in 274 (32.1%) patients, and it was independently associated with significant reduction in ICU mortality (log odds = 0.64 [95% CIs 0.18–1.1; p = 0.0069]) but not an increased risk of critical haemorrhage (log odds = 0.187 [95%CI − 0.591 to − 0.964; p = 0.64]).

Conclusions
In a cohort of critically ill patients with a high prevalence of thromboembolic events, ET was associated with reduced ICU mortality without an increased burden of haemorrhagic complications. This study suggests ET strategies are safe and associated with favourable outcomes. Whilst full anticoagulation has been questioned for prophylaxis in these patients, our results suggest that there may nevertheless be a role for enhanced / intermediate levels of prophylaxis. Clinical trials investigating causal relationship between intermediate thromboprophylaxis and clinical outcomes are urgently needed.