key: cord-0756204-l80ptciw
authors: Tacquard, Charles; Mansour, Alexandre; Godon, Alexandre; Godet, Julien; Poissy, Julien; Garrigue, Delphine; Kipnis, Eric; Hamada, Sophie Rym; Mertes, Paul Michel; Steib, Annick; Ulliel-Roche, Mathilde; Bouhemad, Bélaïd; Nguyen, Maxime; Reizine, Florian; Gouin-Thibault, Isabelle; Besse, Marie Charlotte; Collercandy, Nived; Mankikian, Stefan; Levy, Jerrold H.; Gruel, Yves; Albaladejo, Pierre; Susen, Sophie; Godier, Anne
title: Impact of high dose prophylactic anticoagulation in critically ill patients with COVID-19 pneumonia
date: 2021-01-16
journal: Chest
DOI: 10.1016/j.chest.2021.01.017
sha: b7ac42a2a0d4b93ca6d1539a30db7c0b83a0f81f
doc_id: 756204
cord_uid: l80ptciw

Background Due to the high risk of thrombotic complications (TC) during SARS-CoV-2 infection, several scientific societies have proposed to increase the dose of preventive anticoagulation, although arguments in favor of this strategy are inconsistent. Research question What is the incidence of TC in critically ill patients with COVID-19 and what is the relationship between the dose of anticoagulant therapy and the incidence of TC? Study design and methods All consecutive patients referred to eight French intensive care units (ICU) for COVID-19 were included in our observational study. Clinical and laboratory data were collected from ICU admission to day 14, including anticoagulation status and thrombotic and hemorrhagic events. The effect of high dose prophylactic anticoagulation (either at intermediate or equivalent to therapeutic dose), defined using a standardized protocol of classification, was assessed using a time-varying exposure model using inverse probability of treatment weight. Results Out of 538 patients included, 104 patients developed a total of 122 TC with an incidence of 22.7 % (19.2-26.3). Pulmonary embolism accounted for 52 % of the recorded TC. High dose prophylactic anticoagulation was associated with a significant reduced risk of TC (HR 0.81 [0.66-0.99]) without increasing the risk of bleeding (HR 1.11 [0.70-1.75]). Interpretation High dose prophylactic anticoagulation is associated with a reduction in thrombotic complications in critically ill COVID-19 patients without an increased risk of hemorrhage. Randomized controlled trials comparing prophylaxis with higher doses of anticoagulants are needed to confirm these results.

Patients with severe pneumonia due to SARS-CoV-2 infection, also known as coronavirus 3 disease 2019 (COVID-19), admitted to intensive care units (ICUs) have high rates of 4 thrombotic complications (TC), particularly pulmonary embolism. According to several 5 studies, the proportion of hospitalized patients presenting with TC ranges from 18 to 37%, 6 despite the use of regular prophylactic anticoagulation 1 . The risk of TC appears to be 7 particularly high in critically ill patients admitted to ICUs 2-5 . 8

Although standard pharmacological thromboprophylaxis is recommended in hospitalized 9 patients, several expert groups have proposed to increase anticoagulant dosing in critically ill 10 patients with COVID-19 6 . In particular, the French Working Group on Perioperative 11

Hemostasis (GIHP) and the French Study Group on Thrombosis and Hemostasis (GFHT) have 12

proposed to progressively increase the dose of anticoagulant based on thrombotic risk 13 factors that include obesity, high oxygen demand, need for mechanical ventilation, and 14 biomarkers of major inflammation or hypercoagulability, despite the lack of evidence 15 supporting this strategy 7 . We aimed to study the incidence of thrombotic complications and 16 bleeding in critically ill patients with COVID-19 and examine their relationship to the dose of 17 prophylactic anticoagulation administered. 

We conducted a retrospective chart review of all consecutive adult patients admitted to 3 eight French ICUs for severe laboratory-confirmed COVID-19 pneumonia between March 4 21 st and April 10 th, 2020. The protocol was approved by the University Hospital of Strasbourg 5

Ethics Committee (reference CE-2020-76) and registered at ClinicalTrials.gov 6 (NCT04405869). Partial data from 32 patients from the University Hospital of Strasbourg 7 and 107 from the University Hospital of Lille were previously published 5,8 . 8

Demographic and relevant comorbidities were collected at admission (Day 0). Data regarding 9 clinical management, pharmacologic thromboprophylaxis, laboratory results, and 10 thrombotic and bleeding events were collected for each patient from ICU admission and up 11

to 14 days of follow-up in ICU at 6 prespecified time points (day 1, day 2, day 5, day 8, day 12 11, and day 14), defining 6 different periods of evaluation: admission to day 1, day 1 to day 13 2, day 2 to day 5, day 5 to day 8, day 8 to day 11 and day 11 to day 14 according to the 7 14 predefined time points. For the study purpose, we considered that a patient received 15 pharmacologic thromboprophylaxis during one specific period of evaluation if prophylaxis 16 was reported on the first and last day of that specific period. 17

All patients received pharmacologic thromboprophylaxis for at least one period of 20 evaluation defined as the time between two assessment points. Pharmacological 21 thromboprophylaxis was prescribed according to national guidelines and local protocols of 22 each ICU. Standard prophylaxis was initially recommended using either low molecular 23 weight heparin (LMWH) or unfractionated heparin (UFH) with dosage adjustments for 24 overweight and obese patients 9 . Then, after the GIHP and GFHT published their guidance 25 document (e-table 1) on April 3 rd 2020, doses of thromboprophylaxis were increased 26 according to different risk factors: BMI > 30 kg/m 2 , known risk factor for venous 27 thromboembolism (active cancer, recent personal history of thrombosis, …), catheter or 28 iterative filter coagulation, severe inflammatory syndrome (e.g. fibrinogen > 8 g/l), 29 hypercoagulable state (e.g. D-dimer > 3.0 µg/ml), long-term anticoagulant therapy, and 30

ECMO. The severity of COVID-19 pneumonia, defined by high flow nasal canula or invasive 31 J o u r n a l P r e -p r o o f ventilation requirement, was also a factor in increasing the anticoagulation dose. As our 1 study period ranges from March 21 st to April 10 th , 2020, the doses of prophylactic 2 anticoagulation increased during this period, according to national guidelines, allowing us to 3 compare the two strategies. 4

We retrospectively classified the level of anticoagulation for thromboprophylaxis at each 5 time-point into 2 groups according to the anticoagulant and the dose: standard prophylactic 6 anticoagulation or high prophylactic anticoagulation (which included intermediate and 7

therapeutic dose anticoagulation) (figure 1). For UFH, the level of anticoagulation was 8 defined in terms of anti-Xa activity (when available), which is more accurate than the 9 reported administered dose because the response to UFH is subject to high interpersonal 10 variability. Cumulative treatment coverage was then expressed as the number of evaluation 11 periods covered by anticoagulation before the occurrence of a thrombotic event. were included based on ISTH guidelines and severity was classified according to the GUSTO 19 scale 10 . Patients could only be reported once for each type of thrombotic or hemorrhagic 20 event. Two different thrombotic or hemorrhagic events, e.g. pulmonary embolism and 21 stroke, were considered to be two different types of events, and therefore several events 22 could be reported in the same patient). 23 24

Categorical variables were described by their count and percentage and were compared 26 using Pearson's χ2 tests or Fisher's exact tests. Continuous variables were described by their 27 median with their 1 st and 3 rd quartiles and were compared using nonparametric Wilcoxon 28

Odds-ratio and their 95 % confidence intervals were calculated using logistic regressions to 30 evaluate risk factors for thrombotic complications. A multivariate logistic regression model 31 was used on predictor variables selected from a stepwise model selection based on Akaike 32 information criterion. The selection of variables for the multivariate analysis was based on 1 known risk factors for VTE and COVID-19 pneumonia severity markers. 2

To account for the non-randomized administration of high dose prophylactic anticoagulation 3 and to reduce the effects of confounding factors, the effect of high dose prophylactic 4 anticoagulation on thrombotic complications was analyzed with a time-varying exposure 5 model using inverse probability of treatment weight that allows modelling intermittent 6 treatment exposure 11, 12 . Inverse probability treatment weighting (IPTW) was evaluated using 7 a survival model by using age, sex, body mass index (BMI), smoking status, cardiovascular 8 history, history of long-term anticoagulant treatment as fixed covariates and Sepsis-related 9

Organ Failure Assessment score (SOFA score) and D-dimers as time-varying covariates. These 

A total of 538 ICU patients with confirmed COVID-19 pneumonia were included. admission. The evolution of coagulation parameters within the first two weeks is shown in 14 supplementary materials (e- Figure 1) . 15 16

The overall incidence of TC was 22.7 % (19.2-26.3). During the first 2 weeks of ICU 18 hospitalization, 104 patients experienced a total of 122 TC within a median of 6 [2.5-9] days 19 following ICU admission. The type of TC and their respective incidence are shown in Table 2 . 20

The incidence of TC was particularly high in patients receiving continuous renal replacement 21 therapy (CRRT) or supported by ECMO with an incidence of thrombotic events of 44.8% 22 (32.4-57.5%) and 43.2% (29.2-57.7%), respectively. Conversely, the incidence of TC in 23 patients who had neither CRRT nor ECMO was at 16.5% (13.0-20.2). Risk factors for TC are 24 shown in Table 3 . At ICU admission, D-dimer levels were significantly higher in patients who 25 To our knowledge, this is one of the biggest studies evaluating the effect of higher dosing 2 prophylactic anticoagulation on TC in critically ill patients with COVID-19. Our results indicate 3 that exposure to higher dosing was significantly associated with a reduced risk of TC. 4

In our study, 22.7 % of patients had at least one TC in the first two weeks of ICU 5 hospitalization that were clinically relevant and primarily pulmonary embolism in 52% of the 6 patients with TC. This high incidence of pulmonary embolism is consistent with previous reduction of in-hospital mortality (5.8% vs. 18.8%, p = 0.02). However, this study did not 6 focus on critically ill patients, and groups were not strictly comparable 15 . Thus, there is a lack 7 of evidence to recommend a high dose anticoagulant strategy. We found that cumulative 8 exposure to higher dosing prophylactic anticoagulation was significantly associated with 9 reduced risk of TC, with a hazard ratio of 0.80 [0.65-0.99], which underscores the potential 10 beneficial impact of a higher dosing strategy in critically ill COVID-19 patients. 11

In our study, laboratory data suggested an initial procoagulant profile with 12 hyperinflammation, characterized by increased levels of D-dimer, fibrinogen, FVIII, and von 13

Willebrand Factor antigen. Interestingly, evolution of biomarkers was biphasic, with an initial 14 increase, then a slight decrease. TC mainly occurred during the first phase, whereas bleeding 15 complications were mainly reported during the second phase ( Figure S1 ). Therefore, 16

prophylactic anticoagulation might be adjusted according to the evolution of inflammation. we reported no association between cumulative exposure to higher prophylactic 5 anticoagulation and a bleeding complication. However, the anticoagulant status was 6 unknown in 38.5% of patients as the date of the bleeding event was unavailable, and 7 statistical analysis might be underpowered. 8

Contrary to recently published studies 18,19 , the mortality rate was not influenced by high-9 dose prophylactic anticoagulation in our study. We only recorded the mortality rate on Day 10 14, which in our study was 11.9%, whereas the ICU mortality rate described in these studies 11 ranged from 29.6 to 48.3%. In addition, unlike these studies which only included therapeutic 12 anticoagulation, we also included intermediate-dose anticoagulation in our analysis which 13 may not have been sufficient to influence mortality. 14 Our study has several limitations. First, data collection was limited to the first 14 days. The 15 follow-up period was limited to minimize the contribution of long-term unspecific ICU 16 complications. Indeed, according to pathophysiology of COVID-19 induced thrombosis, 17 hypercoagulability is high within this early period then decreases, and thrombotic events 18 were reported at a median of 6 [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] days after admission to the ICU 20 . Nevertheless, as 19 bleeding events appear to occur later, at a median of 15 [6-25] days after ICU admission 21 , 20 we might have underestimated the incidence of bleeding events. 21

Second, because of the retrospective design of the study, some data were missing, especially 22 those of patients who were the transferred to other ICUs as part of the reorganization of the 23 national healthcare system during the pandemic. 24

The anticoagulation strategy was not standardized among centers, and none of the ICU used 25 a systematic venous thromboembolism screening policy. However, data were sufficiently 26 robust to classify the anticoagulation status of most patients. 27

In conclusion, we showed that high dose prophylactic anticoagulation therapy is associated 29 with reduced TC in critically ill COVID-19 patients, without increasing the risk of bleeding. 30

Randomized controlled trials comparing prophylactic and higher doses of anticoagulants are 1 needed to further confirm these results. 

Thrombosis risk associated with COVID-19 3 infection. A scoping review

Incidence of thrombotic complications in 5 critically ill ICU patients with COVID-19

Prevalence of venous thromboembolism in patients 7 with severe novel coronavirus pneumonia

Incidence of Venous Thromboembolism 9 in Hospitalized Patients with COVID-19

High risk of thrombosis in patients in severe SARS-11

CoV-2 infection: a multicenter prospective cohort study

Anticoagulation practice patterns in COVID-14 19: A global survey

Prevention of thrombotic risk in hospitalized 16 patients with COVID-19 and hemostasis monitoring

Pulmonary Embolism in COVID-19 Patients: 18 Awareness of an Increased Prevalence

Antithrombotic therapy and body mass: an expert 20 position paper of the ESC Working Group on Thrombosis

Definition of major bleeding in clinical investigations of antihemostatic 26 medicinal products in non-surgical patients

A log-rank-type test to compare net survival 29 distributions: A Test to Compare Net Survival Distributions

Ipw: An R Package for Inverse Probability Weighting

Thrombosis in 36 Hospitalized Patients With COVID-19 in a New York City Health System

Association of Treatment Dose Anticoagulation with

Hospital Survival Among Hospitalized Patients with COVID-19

Preliminary Experience With Low Molecular 4 Weight Heparin Strategy in COVID-19 Patients

Deep Vein Thrombosis in Hospitalized Patients With 6 COVID-19 in Wuhan, China: Prevalence, Risk Factors, and Outcome

The impact of obesity on severe disease and mortality 9 in people with SARS-CoV-2: A systematic review and meta-analysis

Press

Intensity of anticoagulation and survival 12 in patients hospitalized with COVID-19 pneumonia

Association of anticoagulation dose and survival in 14 hospitalized COVID-19 patients: A retrospective propensity score-weighted analysis

The impact of protocol-based high-intensity 17 pharmacological thromboprophylaxis on thrombotic events in critically ill COVID-19 18 patients

Thrombotic and haemorrhagic complications in 20 critically ill patients with COVID-19: a multicentre observational study