Design
The present study was a before- (prophylactic)/after- (therapeutic) one: before the evidence of high risk of thrombotic/ischemic events in COVID-19 patients, COVID-19 patients received prophylactic anticoagulation, except if they had an indication for therapeutic anticoagulation; after the publication of the French recommendations in April 2020 (French version) recommending intensification of anticoagulation in COVID-19 patients are high risk of thrombotic/ischemic events, including ICU patients, the two ICUs modified their anticoagulation protocol according to these recommendations [13].
Patients
Between March 3rd and May 30th 2020, all patients referred for ARDS [14] due to SARS‐CoV‐2 were included on admission to two ICUs in two centers of a French tertiary hospital. Patients were managed following current guidelines without specific therapeutic intervention [15]. Approval was obtained from the local ethics committee of the University Hospital of Strasbourg (reference CE-2020-34). All demographic characteristics, medical history, clinical signs, biological and imaging data were prospectively collected. Data were analyzed on August the 10th (i.e., 80 days of follow-up for the most recently admitted patients).
“Prophylactic group” included patients treated with standard or reinforced prophylactic dosage of heparin (low molecular weight heparin LMWH-enoxaparin—up to 6000 IU/12 h SC in obese patients or unfractionated heparin UFH 200 IU/kg/24 h if creatinine clearance < 30 mL/min). Therapeutic anticoagulation included patients who received LMWH at curative dose (100 IU/kg/12 h SC based on actual weight, without exceeding 10,000 IU/12 h or UFH 500 IU/kg/24 h if creatinine clearance < 30 mL/min) according to the French recommendations [13]. Monitoring of anticoagulants was performed according to recommendations [13].
If a patient from the prophylactic group developed a thrombotic/ischemic complication requiring therapeutic dosing of heparin during ICU stay, she/he received the appropriate therapeutic dosing of heparin as soon as the thrombotic/ischemic complication was diagnosed, but she/he was analyzed in the “prophylactic group”.
Patients were excluded if: (i) they were diagnosed with a thrombotic/ischemic event before or on the day of ICU admission; (ii) they had any contra-indication to anticoagulation, (iii) they were already under therapeutic anticoagulation on ICU admission (Fig. 1, flowchart).
Patients under prophylactic anticoagulation at ICU admission were eligible if they had no exclusion criteria.
Two hundred and fifteen consecutive patients, with positive real-time reverse transcriptase PCR tests for COVID-19, admitted to one of the ICUs for ARDS were included in the study. Twenty-six patients diagnosed with a thrombotic event before ICU admission and 10 patients under therapeutic anticoagulation were excluded (Fig. 1, flowchart). No patient was excluded because of contra-indication to anticoagulation.
Outcomes
The primary end-point was to compare the occurrence of any thrombotic/ischemic event in patients admitted in ICU for COVID-19 ARDS in prophylactic and therapeutic groups.
The secondary objectives were: (i) To compare the occurrence of each type of thrombotic/ischemic events occurring during ICU stay: deep vein thrombosis, pulmonary embolism, ischemic stroke, limb/extremity ischemia, myocardial infarction, cerebral stroke, ECMO circuit thrombosis, renal replacement therapy (RRT) device thrombosis; (ii) To compare the occurrence of hemorrhagic events requiring transfusion (grade 3 of World Health Organization bleeding scale) or life-threatening bleeding complication during ICU stay defined by (grade 4 of World Health Organization bleeding scale); (iii) To compare the ICU length of stay and mortality rates; (iv) To compare the effect of anticoagulant treatment on hemostasis in both groups during ICU stay.
Laboratory analysis
Platelet count and coagulation tests were performed daily during the ICU stay, including prothrombin time (PT), antithrombin activity (AT), fibrinogen, D-dimers and activated partial thromboplastin time (aPTT). Factor V (FV), von Willebrand factor (vWF) antigen, vWF activity, and factor VIII (FVIII) activity were performed. Lupus anticoagulant was searched when a coagulation disorder was suspected, based on a prolonged aPTT at ICU admission or on the occurrence of a thrombotic event during ICU stay. Please refer to online supplemental material for further details.
Imaging
CT angiography (pulmonary/abdomino-pelvic/lower limbs) was performed during ICU stay according to clinical or laboratory parameters evolution suggesting thrombosis, as previously described [5]. In particular, according to the following predefined protocol, pulmonary embolism was suspected if PaO2/FiO2 worsened despite inhaled nitric oxide/prone positioning, if hemodynamic was impaired requiring fluid challenge and/or increased norepinephrine infusion rate, evidence of dilated right ventricle—even without acute cor pulmonale, rapid elevation of D-dimer despite anticoagulation.
Patients with suspicion of stroke, based on pathological neurological examination, had either a non-contrast brain CT and/or a brain magnetic resonance imaging (MRI) with diffusion weighted imaging and 3D FLAIR acquisitions.
All CT and MR examinations were read by consultant radiologists specialized in emergency radiology.
Statistics
Continuous variables are presented as median with the first and third quartile and were compared using non parametric Wilcoxon tests. Categorical variables are presented as counts and proportions and were compared using Pearson’s χ2 tests or Fisher’s exact tests. The occurrence of life-threatening thrombotic complications was compared between the groups (prophylactic versus therapeutic) using multivariable logistic regression models. The comparisons were adjusted on the baseline characteristics that were unbalanced between groups or had clinical relevance (age at admission, sex, history of venous thrombo-embolic event, diabetes, chronic renal diseases, PaO2/FiO2 ratio, antiviral treatment, renal replacement therapy, coagulation parameters at admission as d-dimer level, AT, prothrombin time and factor V and UFH). For the comparison of strokes, we used Firth’s bias reduction method to deal with the problem of separation in logistic regression [16, 17]. Results are presented as odds ratio with 95% confidence intervals. Sensitivity analyses were performed using a propensity score. The score was created using a logistic regression model with the treatment variable as the independent variable and the set of adjustment variables from the multivariable model as the dependent variables. The treatment effect was then estimated by adjusting on the propensity score. A p-value < 0.05 was considered as statistically significant. All the analyses were performed using R software version 3.6.1. R Core Team (2019). R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/.