key: cord-0974767-959lpfs0 authors: Atallah, B.; Sadik, Z. G.; Salem, N.; El Nekidy, W. S.; Almahmeed, W.; Park, W. M.; Cherfan, A.; Hamed, F.; Mallat, J. title: The impact of protocol‐based high‐intensity pharmacological thromboprophylaxis on thrombotic events in critically ill COVID‐19 patients date: 2020-11-05 journal: Anaesthesia DOI: 10.1111/anae.15300 sha: b552fd959b39ff0c66d60e5825916e072ed441e3 doc_id: 974767 cord_uid: 959lpfs0 The reported incidence rate of venous and arterial thrombotic events in critically ill patients with COVID‐19 infections is high, ranging from 20% to 60%. We adopted a patient‐tailored thromboprophylaxis protocol based on clinical and laboratory presentations for these patients in our institution. We hypothesised that patients who received high‐intensity thromboprophylaxis treatment would experience fewer thrombotic events. The aims of our study were to explore the incidence of thrombotic events in this population; to assess independent factors associated with thrombotic events and to evaluate the incidence of haemorrhagic events. A retrospective review of all adult patients with confirmed SARS‐CoV‐2 infection admitted to the intensive care unit (ICU) between 1 March and 29 May 2020 was performed. The primary outcome was a composite of venous and arterial thrombotic events diagnosed during the ICU stay. Multivariable logistic regression was used to identify the independent factors associated with thrombotic events. A total of 188 patients met the inclusion criteria. All received some type of thromboprophylaxis treatment except for six patients who did not receive any prophylaxis. Of the 182 patients who received thromboprophylaxis, 75 (40%) received high‐intensity thromboprophylaxis and 24 (12.8%) were treated with therapeutic anticoagulation. Twenty‐one patients (11.2%) experienced 23 thrombotic events (incidence rate of 12.2% (95%CI 7.9–17.8)), including 12 deep venous thromboses, 9 pulmonary emboli and 2 peripheral arterial thromboses. The multivariable logistic regression analysis showed that only D‐dimer (OR 2.80, p = 0.002) and high‐intensity thromboprophylaxis regimen (OR 0.20, p = 0.01) were independently associated with thrombotic events. Thirty‐one patients (16.5%) experienced haemorrhagic events; among them, 13 were classified as major bleeding according to the International Society on Thrombosis and Haemostasis criteria. Therapeutic anticoagulation, but not the high‐intensity thromboprophylaxis regimen, was associated with major bleeding. A proactive approach to the management of thromboembolism in critically ill COVID‐19 patients utilising a high‐intensity thromboprophylaxis regimen in appropriately selected patients may result in lower thrombotic events without increasing the risk of bleeding. The SARS-CoV-2 pandemic has resulted in an influx of patients to hospitals and intensive care units (ICU) globally. While the respiratory manifestations and cytokine storm associated with this virus have been the main concern, the underlying involvement of other organs and systems has also been the subject of much interest and the reason why some patients succumb to the illness [1, 2] . In particular, the unique haematologic presentations observed in some of the sickest patients and the high incidence of thrombotic events have led to a global effort to identify optimal proactive management strategies [3] [4] [5] . The haematologic changes reported in COVID-19 (including prolongation of prothrombin time and activated partial thromboplastin time, elevations of D-dimers and fibrinogen and a mild to moderate thrombocytopenia) are not identical to that of acute disseminated intravascular coagulopathy which is commonly seen in ICU [5, 6] . This is supported by the fact that while some of these haematologic abnormalities may mimic disseminated intravascular coagulopathy, the most common manifestation of COVID-19 coagulopathy is thrombosis rather than bleeding with a high incidence of thrombotic events in critically ill patients [2, 5, [7] [8] [9] . A recent multinational consensus statement from the International Society on Thrombosis and Haemostasis highlighted the high incidence of venous thromboembolism, the severity of the occurrence, and called for a systematic approach to venous thromboembolism prevention, diagnosis and treatment for patients with COVID-19 [10] . At our institution, we adopted an anticoagulation protocol that provides a patient-tailored algorithm, utilising stratification based on clinical and laboratory presentations, balancing bleeding and thrombotic risk. While the cut-off values for these diagnostic tests and the response to them continues to be modified as more data emerge, we derived risk stratification values based on the available evidence [11, 12] . We hypothesised that patients who received highintensity thromboprophylaxis treatment would experience fewer venous and arterial thrombotic events. The aims of our study were to explore the incidence of thrombotic events in our critically ill COVID-19 patients; to assess factors that are independently associated with thrombotic events and to evaluate the incidence of the occurrence of haemorrhagic events. [13] . Patients who were deemed at high risk for bleeding (defined as venous thromboembolism bleed score > 2 [14] ) (see online Supporting Information Appendix S1), platelet count < 50 9 10 9 .l À1 or INR > 2, were not included. Similar were not reported or included in the analysis. A receiver operating characteristics (ROC) curve was constructed to evaluate D-dimer's ability to predict thrombotic events. The best cut-off for a ROC curve was chosen with the highest Youden index [15] . Sensitivity, specificity, positive predictive value, negative predictive value and their 95%CIs were calculated for the best cut-off value. A multivariable logistic regression analysis was used to identify significant independent factors that were associated with thrombotic events. Variables that were associated with thrombotic events (p < 0.1) in univariate analysis, and that are known to influence the thrombotic event occurrence, were entered in the model. The potential problem of co-linearity was evaluated using Spearman or Pearson correlation coefficient before running the analysis. Goodness of fit of the model was assessed using the Hosmer-Lemeshow's test. A value of p < 0.05 was considered statistically significant and all reported p values are two-sided. From 1 March to 29 May 2020, 188 adult patients with COVID-19 were admitted to ICU and included in this study ( Fig. 2) . The main characteristics of the cohort are summarised in Table 1 . differences were found in baseline characteristics between patients who did and did not experience thrombotic events except for the D-dimer level, which was significantly higher in the thrombotic events group (Table 1) . Invasive mechanical ventilation, prone position and vasopressor support were not significantly associated with thrombotic events although the use of neuromuscular blocking drugs was significantly higher in those who had thrombotic events (52.4% vs. 30.5%, p = 0.045). The use of high-intensity thromboprophylaxis was higher in the non-thrombotic events group (40.7%) than in the thrombotic events group (28.6%); however, thromboprophylaxis regimen was not significantly associated with thrombotic events. There was no difference in ICU mortality and duration of mechanical ventilation between the two groups although the median ICU length of stay was significantly longer in the thrombotic events group ( Multivariable logistic regression analysis was performed to determine the factors that were independently associated with the occurrence of thrombotic events. In the univariate analysis (Table 1) , D-dimer, invasive mechanical ventilation, neuromuscular blocking drugs and extracorporeal membrane oxygenation were associated with thrombotic events (p < 0.1). Thus, these variables were entered into the multivariable model. Thromboprophylaxis regimen was also included in the model, even if it was not statistically associated with thrombotic events (p > 0.1), as it is a well-known factor that can influence the thrombotic events occurrence. Table 2 shows the results of the multivariable analysis. Table S1 ). The ability of D-dimer max to predict thrombotic events occurrence was acceptable with area under the ROC curve of 0.730 (95%CI 0.659-0.793) (Fig. 3) . The best cut-off value (according to Youden index) was > 3.93 µg.ml À1 (95%CI: >3.84 µg.ml À1 to > 3.93 µg.ml À1 ) with a sensitivity of 86% In our COVID-19 ICU patients, we found that the overall incidence of thrombotic events was 12.2% and that Ddimers were independent predictors of thrombotic events. The use of high-intensity prophylactic treatment was associated with a lower incidence of thrombotic events without increasing major bleeding. However, therapeutic anticoagulation was associated with major bleeding. The impact of COVID-19 on coagulation and haemostasis is multifactorial and includes systemic inflammation and activation of the complement system (cytokine storm). Heparin is known to have a role as an anti-inflammatory agent through mechanisms that include binding to inflammatory cytokines [16] [17] [18] [19] as well as its inherent anticoagulant properties. It also potentially prevents viral attachment through binding to host or viral glycoproteins [20] . The overall thrombotic rate observed in our study of 12.2% is lower than that previously reported with severe COVID-19 in ICU, which has ranged from 20% to 69% [5, 7-921-26] . [26, 28] . We found that a D-dimer value of 1.57 µg.ml À1 had an excellent negative predictive value (98%) to rule out thromboembolism. This value of D-dimer is close to that in our hospital protocol (2 µg.ml À1 ) on which we base the decision to use a high- Figure 4 Results of inflammatory and coagulation markers between ICU admission and time of thromboembolic thromboembolic (TE) events in thromboembolic and non-thromboembolic groups.*p < 0.025 between thromboembolic and non-thromboembolic comparisons (Bonferroni method). # p < 0.05 within-group comparisons. Data are median (IQR). intensity thromboprophylaxis regimen (Fig. 1 [9] where therapeutic anticoagulation was used. The rate of major bleeding among these haemorrhagic events was high (77%) [9] . Therefore, we cannot recommend the liberal use of therapeutic anticoagulation in critical COVID-19 patients. Our study is the first to demonstrate the utility and safety of a patient-tailored thromboprophylaxis regimen with a high-intensity prophylactic dosage based on a Ddimer level to reduce the rate of thrombotic events in critically ill COVID-19 patients. In addition, therapeutic anticoagulation was associated with a higher rate of major bleeding without decreasing thrombotic events rate. However, further studies are needed to confirm our findings. Our study has some important limitations. It is a singlecentre retrospective study conducted at a quaternary care facility in the Middle East, and thus management and outcomes do not necessarily reflect those at other centres. Less than half of the patients underwent imaging for thrombotic events, which may have resulted in missing events in some patients. Also, we did not include central venous and haemodialysis catheter-related thrombosis as part of thrombotic events. This might, in part, explain the lower observed rate of thrombotic events in our study than previously reported. However, even though many ICUs observed an increase in such thrombosis in COVID-19 patients, its real incidence is still unknown. While we implemented an institutional protocol that prompts providers to order imaging based on D-dimer cut-off values (D-dimer > 3 µg.l À1 , Fig. 1 ), the ultimate decision to prescribe anticoagulation was still at the discretion of the provider. 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Protocol: Information related to the Institutional thromboprophylaxis protocol. Table S1 . Results of the multivariate logistic regression results when D-dimer value on admission was included in the model instead of max D-dimer.