Background
A growing body of observational clinical evidence indicates that coronavirus disease (COVID‐19) is associated with a high incidence of thrombotic complications [
1‐
4]. Despite standard anticoagulant thromboprophylaxis, the burden of thrombotic complications—primarily pulmonary embolism (PE)—remains high in COVID-19 patients, in particular among those requiring intensive care unit (ICU) admission. Recent studies on COVID-19 patients have reported an incidence of thromboembolic events ranging from 27 to 57% [
5] despite standard thromboprophylaxis, and a recent review of studies including a total of 1765 hospitalised patients (mixed cohort of patients admitted to the ICU or the ward) reported the occurrence of venous thromboembolism (VTE) in approximately 20% of patients, with cumulative prevalence up to 49% during hospitalisation [
6].
Although observational clinical data suggest that the use of either prophylactic to increased doses of low molecular weight heparins (LMWH) in high-risk patients may be associated with better prognosis, the optimal thromboprophylaxis strategy in the critically ill COVID-19 patient population remains uncertain [
7]. In the absence of evidence from randomised controlled trials, published guidance based on observational data and expert opinion has been heterogeneous and sometimes contradictory, ranging from standard treatment to a variety of ET protocols with varying levels of anticoagulation from enoxaparin 40 mg BD to full therapeutic anticoagulation with unfractionated heparin [
8‐
11]. Recently, three randomised clinical trials aimed to test the effects of full doses of anticoagulants in COVID-19 patients have paused enrolment for futility, questioning the benefit of giving full dose anticoagulants routinely in critically ill COVID-19 patients and raising concerns regarding the safety of widespread ET protocols [
12].
The purpose of this study was therefore to describe the prevalence of ET strategies in European Intensive Care Unit (ICUs) and to assess their association with ICU mortality and safety in a large cohort of critically ill COVID-19 patients admitted to European ICUs during the first wave of the pandemic.
Discussion
We report on the wide adoption of empirically ‘enhanced' thromboprophylaxis strategies for critically ill COVID-19 patients during the first wave of the pandemic. These enhanced strategies varied among European centres. The most common strategy consisted in increasing LMWH prophylaxis to an intermediate range between standard prophylaxis and full therapeutic anticoagulation. A minority of centres opted for full therapeutic anticoagulation with unfractionated heparin.
The main finding of this study is that the introduction of ‘enhanced thromboprophylaxis’ strategies was not associated with an increased incidence of haemorrhagic events and it was associated with increased ICU survival in propensity matched analysis.
These findings are of particular relevance in view of the recent suspension on the grounds of futility for three clinical trials investigating the effects of full doses of anticoagulants in critically ill COVID-19 patients [
12].
The association of intermediate ‘enhanced thromboprophylaxis’ strategies with the improved survival in the absence of increased haemorrhagic complications suggests that standard approaches may safely be augmented. Whilst caution needs to be employed given the non-random allocation and variances in practice and we do not claim statistical significance, the survival curve of Fig.
1 is consistent with the improved survival with ET found in the propensity matched model.
Dysregulated coagulation, systemic prothrombotic state and local micro-thrombosis associated with acute endothelial inflammation, hypoxia, apoptosis and platelet activation are the main pathophysiological mechanisms underlying COVID-19-related coagulopathy [
1‐
4].
There is fairly convincing evidence that in situ pulmonary artery microthrombi may partly represent the endpoint of pulmonary inflammation [
6,
19].
Based on such aetiological considerations, it would seem reasonable to assume that therapeutic interventions should primarily target the early stages of the process (i.e. inflammation modulation and inhibition of platelet activation) rather than the coagulation cascade (thus discounting the potential benefits of heparin-based treatments) [
20]. Moreover, if microvascular coagulation occurs as a manifestation of end-stage lung inflammation, alveolar damage and hypoxia (i.e. pulmonary thrombosis seen as a tombstone rather than a risk factor for cardiocirculatory collapse, respiratory failure and fatal outcome), then anticoagulation or thrombolysis would incur the risk of precipitating pulmonary haemorrhage without proving any benefit [
20].
Whilst it is not disputed that immunomodulation and inhibition of platelet activation are certainly key targets for the care of critically ill COVID-19 patients [
21] (dexamethasone is the only drug clearly proven to reduce mortality at the time of writing [
20]), our results support the use of ET strategies. Although the mechanisms of heparin resistance in critically ill COVID-19 patients remain to be fully elucidated, the phenomenon has been clearly described and could be at least partially attributed to high factor VIII and fibrinogen and low antithrombin levels typically seen in these patients [
23]. Heparin resistance with unfractionated heparin or sub-optimal anti-Xa peak with low molecular weight heparin was confirmed to be a common occurrence. It was furthermore confirmed that in vitro spiking of COVID-19 samples from patients in intensive care unit with low molecular weight heparin failed to recover the anti-Xa level as would have been predicted [
24]. In conjunction with the evidence of high rate of thromboembolic events despite standard thromboprophylaxis, the evidence of heparin resistance supports the implementation of increased prophylactic dosing in critically ill COVID-19 patients [
21].
Furthermore, preliminary studies reported a significant reduction in thromboembolic events for critically ill COVID-19 patients treated with empirical ET strategies when compared to standard prophylaxis (
N = 26, 56% vs 100%,
p = 0.03) [
22]. These findings replicate earlier experience in patients developing ARDS secondary to influenza A [H1N1], where empirical ‘therapeutic’ heparin prophylaxis was associated with a 33-fold reduction in thromboembolic events, crucially in the absence of increased haemorrhagic complications [
23].
Massive pulmonary embolism may be a potentially reversible cause of death and therefore a potential therapeutic target in critically ill COVID-19 patients. A case series of post-mortem autopsies found that venous thromboembolism was present in 7 of 12 (58%) patients with COVID-19. The study concluded that pulmonary embolism had been the direct cause of death in a third of cases [
15]. This is consistent with our findings of a high prevalence of pulmonary embolism and sudden cardiocirculatory collapse and respiratory failure as the most prevalent modes of death. Whether this process can be prevented or reversed remains to be proven, but in a series of three patients with severe COVID-19 respiratory failure who were treated with tissue plasminogen activator a temporally related improvement in respiratory status was reported in all cases (with one of them being a durable response) suggesting a potential reversibility of the process [
24].
Risk of haemorrhage
A French single centre study on 92 critically ill COVID-19 patients reported a 40% prevalence of thromboembolic events (TE) and a 21% rate of ‘significant’ thromboembolic events, with most of such events occurring in patients being treated with full dose anticoagulation. The authors concluded:
“as half of these patients were treated with full-dose pre-emptive anticoagulation without a confirmed TE, we must be cautious about our thromboprophylaxis strategy with daily reassessment of its indication” [
25]. Whilst we echo the call for caution, the findings of our study seem to indicate that the use of ET is
not associated with an increased chance of death or critical haemorrhagic events.
Practical considerations
Given the high burden of thromboembolic complications associated with standard prophylaxis and the absence of major haemorrhage related mortality, the implementation of ‘enhanced’ thromboprophylaxis strategies seems justified. Whilst the ideal dosing and stratification remains to be determined by randomised clinical trials, the implementation of twice daily standard LMWH prophylaxis appears to be reasonable and has the advantage of limiting staff exposure when compared to continuous UFH infusion and aPTT monitoring. In view of the prevalence of renal impairment in this patient population, careful dose adjusting and anti-Xa and aPTT-ratio monitoring is strongly recommended. Given the high prevalence of thromboembolic events even in the absence of risk factors [
26] and in consideration of limited validation for risk stratification tools, the authors support a standard ‘universal’ approach to ‘enhanced thromboprophylaxis’ for critically ill COVID-19 patients.
Limitations of the study
Our study also has several important limitations. Firstly, being a retrospective observational dataset, no definite conclusions can be taken in regard to what the ideal thromboprophylaxis strategy for critically ill COVID-19 patients should be as it is impossible to be sure that the propensity score captures the true decision making in instituting ET in an observational dataset. Secondly, as this is an observational and not interventional study, each centre relied on its own screening methods for the detection of thromboembolic complications, without a systematic screening of patients for haemorrhagic and thrombotic events. Also, we limited our observations and anticoagulant therapy at admission and in the early phases of ICU admission, thus reducing the potential effect of long-term anticoagulant strategies. Moreover, the multicentric nature of the study could potentially increase variance and data integration difficulties among different centres, which is simply not possible to correct by means of post hoc analysis. Whilst clearly not as robust in demonstrating causality as a well conducted randomised controlled trial, our propensity score method attempts to exploit ‘natural’ variations in practice within and between sites to remove bias from the ET cohort.
Acknowledgements
The authors would like to acknowledge as collaborators the following authors.
Nicole Innerhofer: Department of Anaesthesia and Intensive Care, University Hospital Innsbruck (Austria). Sara Miori: Anestesia e Rianimazione Ospedale Santa Chiara APSS – Trento (Italy). Alberto Librizzi: Anestesia e Rianimazione, Spedali Civili, Brescia (Italy). Rita Bertuetti: Anestesia e Rianimazione, Spedali Civili, Brescia (Italy). Nicolas Figueiredo Faria: Hopital Erasme, Bruxelles (Belgium). Lorenzo Peluso: Hopital Erasme, Bruxelles (Belgium). Giorgia Montrucchio: Rianimazione CAR di Città della Salute e della Scienza di Torino (Italy). Gabriele Sales: Rianimazione CAR di Città della Salute e della Scienza di Torino (Italy). Luca Brazzi: Rianimazione CAR di Città della Salute e della Scienza di Torino (Italy). Daniela Alampi: Ospedale sant’andrea di Roma, Universita Sapienza (Italy). Maria Beatrice Manca: Ospedale sant’andrea di Roma, Universita Sapienza (Italy). Lilia Sepe: Department of Anesthesia and Intensive Care, POLIAMBULANZA FOUNDATION, Brescia (Italy). Giuseppe Natalini: Department of Anesthesia and Intensive Care, POLIAMBULANZA FOUNDATION, Brescia (Italy). Antonio Bellino: Department of Anesthesia and Intensive Care, POLIAMBULANZA FOUNDATION, Brescia (Italy). Maria Grazia Bocci: Dipartimento di Scienze dell'Emergenza, Anestesiologiche e della Rianimazione Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, (Italy). Chiara Mattana: Dipartimento di Scienze dell'Emergenza, Anestesiologiche e della Rianimazione Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, (Italy). Francesco Corradi: Department of Anesthesia and Intensive Care, University of Pisa, (Italy). Francesco Forfori: Department of Anesthesia and Intensive Care, University of Pisa, (Italy). Francesco Cundari: Department of Anesthesia and Intensive Care, University of Pisa, (Italy). Emilio Bonvecchio: Anestesia e Rianimazione, Università degli Studi di Milano Statale, (Italy). Zara Busani: Anestesia e Rianimazione, Università degli Studi di Milano Statale, (Italy). Andrea Bianchin: U.O. Anestesia e Rianimazione, Ospedale S.Valentino Montebelluna, Azienda ULSS 2 Marca Trevigiana, (Italy). Carla Federico: U.O. Anestesia e Rianimazione, Ospedale S.Valentino Montebelluna, Azienda ULSS 2 Marca Trevigiana, (Italy). Anna Santoro: Anestesia e Rianimazione, Città della Salute e della Scienza di Torino, (Italy). Federico Bilotta: Department of Anesthesiology, Critical Care and Pain Medicine, Policlinico Umberto I, "Sapienza" University of Rome, Rome, (Italy). Giorgio Rajani: Department of Anesthesiology, Critical Care and Pain Medicine, Policlinico Umberto I, "Sapienza" University of Rome, Rome, (Italy). Berta Moleon Lopez: Department of Anesthesia and Intensive CareUniversity of Valencia, (Spain). Raffaele Aspide: IRCCS Istituto delle Scienze Neurologiche di Bologna, Anesthesia and Neurointensive Care Unit, Bologna, (Italy). Merola Raffaele: Università di Bologna, Dipartimento di Scienze Mediche e Chirurgiche, Anesthesia and Intensive Care Medicine, Policlinico di Sant’Orsola, Bologna, (Italy). Luca Cabrini: Presidio Ospedale di Circolo e Fondazione Macchi, Varese, (Italy). Alessandro Motta: Presidio Ospedale di Circolo e Fondazione Macchi, Varese, (Italy). Lara Frattini: Presidio Ospedale di Circolo e Fondazione Macchi, Varese, (Italy). Alexandre Godon: Department of Anesthesia and Intensive Care, Grenoble (France). Pierre Bouzat: Department of Anesthesia and Intensive Care, Grenoble (France). Elena Grappa: UOS Neuroanestesia, UOC Anestesia e Rianimazione ASST Cremona, (Italy). Alberto Bonvecchio: UOS Neuroanestesia, UOC Anestesia e Rianimazione ASST Cremona, (Italy). Nicole Innerhofer: Department of General and Surgical Intensive Care Medicine, Medical University Innsbruck, Innsbruck, Austria. Dietmar Fries: Department of General and Surgical Intensive Care Medicine, Medical University Innsbruck, Innsbruck, Austria. Christian Preuss Hernandez: epartment of Neurosurgery, Medical University Innsbruck, Innsbruck, Austria. Claudius Thomé: Department of Neurosurgery, Medical University Innsbruck, Innsbruck, Austria. Sebastian Klein: Division of Intensive Care and Emergency Medicine, Department of Internal Medicine, Medical University Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria. Michael Joannidis: Division of Intensive Care and Emergency Medicine, Department of Internal Medicine, Medical University Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria. Paolo Pelosi: Dipartimento di Scienze Chirurgiche e Integrate, University of Genova, Italy. Lorenzo Ball: Dipartimento di Scienze Chirurgiche e Integrate, University of Genova, Italy. Iole Brunetti: Policlinico San Martino, IRCCS for Oncology and Neuroscience, Genova, Italy. Nicolo’ Patroniti: Dipartimento di Scienze Chirurgiche e Integrate, University of Genova, Italy. Matteo Bassetti: Infectious Diseases Unit, Ospedale Policlinico San Martino, IRCCS, Genoa, Italy. Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy. Daniele Roberto Giacobbe: Infectious Diseases Unit, Ospedale Policlinico San Martino, IRCCS, Genoa, Italy. Antonio Vena: Infectious Diseases Unit, Ospedale Policlinico San Martino, IRCCS, Genoa, Italy. Alberto Valbusa: Dipartimento CardioToracoVascolare Ospedale Policlinico San Martino IRCCS, Genoa, Italy. Italo Porto: Dipartimento CardioToracoVascolare Ospedale Policlinico San Martino IRCCS, Genoa, Italy. Roberta Della Bona: Dipartimento CardioToracoVascolare Ospedale Policlinico San Martino IRCCS, Genoa, Italy.
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