key: cord-0741248-mxgp65jp authors: Gabara, Cristina; Solarat, Belen; Castro, Pedro; Fernández, Sara; Badia, Joan Ramon; Toapanta, David; Schulman, Sam; Reverter, Juan Carlos; Soriano, Alex; Moisés, Jorge; Aibar, Jesús title: Anticoagulation strategies and risk of bleeding events in critically ill COVID-19 patients date: 2021-07-30 journal: Med Intensiva DOI: 10.1016/j.medin.2021.07.004 sha: 55f0b58042f27da8ca51d971194a224f3afc01cd doc_id: 741248 cord_uid: mxgp65jp Objective: To evaluate the rate of thrombosis, bleeding and mortality comparing anticoagulant doses in critically ill COVID-19 patients. Design: Retrospective observational and analytical cohort study. Setting: COVID-19 patients admitted to the intensive care unit of a tertiary hospital between March and April 2020. Patients: 201 critically ill COVID-19 patients were included. Patients were categorized into three groups according to the highest anticoagulant dose received during hospitalization: prophylactic, intermediate and therapeutic. Interventions: The incidence of venous thromboembolism (VTE), bleeding and mortality was compared between groups. We performed two logistic multivariable regressions to test the association between VTE and bleeding and the anticoagulant regimen. Main variables of interest: VTE, bleeding and mortality. Results: 78 patients received prophylactic, 94 intermediate and 29 therapeutic doses. No differences in VTE and mortality were found, while bleeding events were more frequent in the therapeutic (31%) and intermediate (15%) dose group than in the prophylactic group (5%) (p<0.001 and p<0.05 respectively). The anticoagulant dose was the strongest determinant for bleeding (odds ratio 2.4, 95% confidence interval 1.26-4.58, p=0.008) but had no impact on VTE. Conclusions: Intermediate and therapeutic doses appear to have a higher risk of bleeding without a decrease of VTE events and mortality in critically ill COVID-19 patients. The coronavirus disease 2019 (COVID-19) pandemic is responsible for high intensive care unit (ICU) admission rates and high mortality [1] [2] [3] . COVID-19 is also associated to a high risk of venous thromboembolism (VTE) and a significant coagulopathy that correlates with disease severity [1, 3, 4] . In this sense, high D-dimer levels, fibrinogen and C-reactive protein (CRP), as well as prolonged prothrombin time (PT), have been associated with increased need of ICU admission and worse outcomes [1, 4, 5] . Previous studies have described a rate of VTE in ICU patients on standard-dose VTE prophylaxis that varies between 7.6% and 69% [2, 5, 6] . Recent studies have suggested a decreased mortality associated with anticoagulant treatment in severe COVID-19 [4, 7, 8] . Consequently, the Italian Medicines Agency and some thrombosis Medical Societies recommend the use of intermediate-dose VTE prophylaxis in selected patients with major risk of thrombosis (ICU patients, weight over 80 kg or high D-dimer levels) [9] [10] [11] . Remarkably, Al-Samkari and colleagues found that elevated D-dimer levels at admission predicted not only thrombotic complications, critical illness and death, but also bleeding complications [5] . Due to these findings, it has been postulated that the elevated D-dimer levels, thrombotic manifestations and bleeding events are related to a coagulation system activation in the setting of severe inflammation and that local thrombi both in the lungs and other organs, rather than emboli from peripheral veins, appear to be the hallmark of severe COVID-19 [12] . In fact, post-mortem studies have highlighted marked pathological changes involving the lung microvasculature, including disseminated microthrombi and significant haemorrhagic necrosis [13] , which suggest that the diffuse Page 8 of 28 J o u r n a l P r e -p r o o f 8 bilateral pulmonary inflammation observed in COVID-19 is associated with a novel pulmonary-specific vasculopathy termed pulmonary intravascular coagulopathy [1] In consequence, considering that therapeutic doses of heparin are not indicated for treatment of other types of thrombotic microangiopathies, higher than prophylactic doses of heparin may not be more effective preventing VTE and can yield an increased risk of bleeding (especially in critically ill patients who have major thrombosis risk, but also high bleeding risk [14] , thereby worsening their prognosis. We conducted an observational and analytical retrospective cohort study at a university hospital in Barcelona. All patients consecutively admitted to the ICU of the Hospital between March 1 and April 30, 2020, aged > 18 years old and with confirmed diagnosis of COVID-19 infection (defined as a positive SARS-CoV-2 reverse-transcriptase polymerase chain reaction test by nasopharyngeal/oropharyngeal swab or sputum specimen) were included. Patients without a confirmed COVID-19 infection were excluded. Patient' data were obtained retrospectively and included: demographics, relevant comorbidities, invasive and non-invasive mechanical ventilation, bleeding events, venous thrombotic events, anticoagulation administered and mortality during the hospitalization. We also included inflammatory laboratory parameters (D-dimer, CRP, lactate dehydrogenase [LDH] and ferritin) at admission and at time of bleeding and thrombotic events. The local institutional ethics committee approved the study, waiving the need for informed consent from individual patients because of its retrospective nature (HCB/2020/0273). Patients were categorized in three groups depending on the highest anticoagulant dose they received during the hospitalization, administered for at least 2 days, prior to a VTE patients. According to this protocol, prophylactic doses were recommended for all COVID-19 patients who require hospital admission. Intermediate or therapeutic doses were recommended for patients with body weight >80 kilograms, patients with an added risk factor for VTE (cancer, previous VTE, thrombophilia, recent surgery, pregnancy or use of estrogens) or patients who had a persistent high D-dimer level (> 3,000 ng/ml) dissociated from other inflammatory parameters (CRP, ferritin). The decision of using intermediate or therapeutic dose was taken by the medical team responsible for the patient. Table 1 summarizes the different doses used. Haemostasis definition, being categorized as major bleedings those with the following criteria: 1) Fatal bleeding, and/or 2) Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome, and/or 3) Bleeding causing a fall in haemoglobin level of 20 g/L) or more, or leading to transfusion of two or more units of whole blood or red cells [15] . Pulmonary embolism (PE) and deep vein thrombosis (DVT) were confirmed with a CT pulmonary angiogram (CTPA) and Doppler ultrasound respectively when there was a clinical suspicion. Synchronously diagnosed DVT and PE in the same patient were considered one VTE event. Continuous variables are presented as mean with standard deviation (SD), while categorical or binary data are shown as frequencies and proportions. To compare the demographics, clinical characteristics, incidence of VTE, bleeding and mortality depending on the anticoagulant regimen we used the chi-squared or Fisher's exact tests for categorical data, and the ANOVA test for quantitative continuous data. Pairwise comparisons were performed with chi-squared or Fisher's exact tests for categorical data and with Student's t-test and corrected by Bonferroni test when continuous data was analysed. with and without thrombotic complications; as well as in patients with and without bleeding complications using the Mann-Whitney U test. We performed 3 Kaplan-Meier curves, using the Log-rank test, in order to compare the cumulative incidence of VTE, bleeding and mortality between groups (prophylactic, intermediate and therapeutic anticoagulant doses). We performed a logistic multivariable regression to test the association between VTE or bleeding and clinical characteristics as well as the anticoagulant regimen. The A total of 201 patients were included. Their mean age was 62 years (SD 12.9) and 142 (71%) were males. 82% of the patients had at least one comorbidity, the most frequent ones being: hypertension (54%), dyslipidaemia (33%), diabetes (19%), pulmonary disease (17%) and heart disease (17%). 15 patients (7.5%) were on therapeutic anticoagulant treatment before the admission: 10 (67%) for atrial fibrillation, 3 (20%) for VTE, 1 (6%) for mechanical aortic valve prosthesis and 1 (6%) for Antiphospholipid syndrome. From A total of 112 patients (56%) required IMV and 31 (15%) needed non-invasive mechanical ventilation. There were no statistically significant differences in the anticoagulant regimens between patients who required IMV and the ones who did not (p=0.25). There were no significant differences in VTE between subjects with or without IMV (23% vs 17%, p=0.29). Subjects requiring IMV presented more bleeding events than patients who did not (20% vs 6%, p=0.004). Bleedings in those requiring IMV were mostly major bleeds (59%), being the most frequent sites of them the CNS (25%), muscular hematoma (25%) and retroperitoneal (20%). The overall in-hospital mortality was 20%, out of which 80% were related with COVID-19 complications. In-hospital mortality was higher in patients with VTE than in those without VTE, but there was not a statistically significant difference (10% vs 24%; p=0.054). There were also no differences in the mortality rate between patients with and without bleeding complications (26% vs 20%, p= 0.46). The characteristics of the patients depending on the anticoagulant dose received Table 2 . We performed 3 Kaplan-Meir curves in order to analyze the differences in cumulative incidence of VTE, bleeding and mortality (Figure 1 ). We found statistical significant J o u r n a l P r e -p r o o f 17 differences between groups in bleeding events (p=0.014), but not in VTE (p=0.91) and mortality (p=0.52). Finally, to assess whether the anticoagulant dose and other clinical characteristics influence the risk of VTE and bleeding, a logistic regression analysis was performed ( group were older than the ones of the prophylactic group. These results may be explained by the fact that older people usually present higher D-dimer levels than young people [16] and, in consequence, due to the indication of higher anticoagulant doses when D-dimer levels were > 3,000 ng/ml, older people could have been more susceptible to receive higher doses. We found an overall VTE rate of 20%, which is consistent with previous data in the literature [2, 5, 6] . PE was the most frequent form of presentation (80%), but it is important to remark that 80% of them were peripheral, which might not have the same clinical relevance as a central PE. When we explored the prevalence of VTE in the different anticoagulant groups, we did not find significant differences. Taking into In contrast to numerous reports assessing the high prevalence of VTE, only few studies have reported bleeding rates. These rates vary between 3-7.6% using prophylactic doses [5, 7] , and between 1.9-21.4% [17, [19] [20] [21] with higher anticoagulant doses. Our results show a high bleeding rate (13%), including a high rate of major bleedings (8%), especially in patients receiving therapeutic anticoagulant doses. These results differ from those obtained by Mattioli et al [19] , who described lower rates (1.9% of major bleeding) in a cohort of 105 hospitalized patients with intermediate dose. Nevertheless, it is important to note that while these were not strictly ICU patients, the authors report that 6.7% of the patients needed transfusion of red blood cells, which can signal that the rate of overall haemorrhage was higher. A higher incidence, and more similar to our results, has been reported by Kessler and colleagues [20] , who reported 6% of major We also found an association between the need of IMV and bleeding, which is consistent with the results obtained with Paranjpe et al [7] who describe higher bleeding rates in intubated patients than in non-intubated patients. This association may be in relation to disease severity. In contrast, we did not find any association between the anticoagulant regimen and VTE events. We found no differences in mortality rates between groups, contrary to the results obtained by Jonmarker S et al. [8], who described a 67% decreased risk of death the first 28 days among those who received high vs low dose prophylaxis, without a major rate of bleeding. These differences can be partially explained because in our study, we followed patients until hospital discharge (not only the first 28 days), so we registered later bleeding events and mortality related with complications due to large hospitalization period. In contrast, our results are consistent with dose obtained in the INSPIRATION Randomized Trial [18] and with those described in a pre-print article based on a recent international multiplatform randomized clinical trial, which concludes that therapeutic anticoagulation did not improve hospital survival in sever Covid-19 patients compared with standard doses [21] . Nevertheless, due to the fact that higher anticoagulant doses are probably given to patients that are at highest risk of VTE, the absence of differences of VTE between groups could mean that with higher doses we may be preventing these patients of a VTE event that, otherwise, could have happened. In this sense, when suspected, the confirmation of the VTE events radiologically is important to adequate as soon as possible the anticoagulant dose. Overall, it seems that intermediate anticoagulant doses may present a better benefit-risk profile in critically ill COVID-19 patients than the prophylactic and therapeutic doses, being able to prevent VTE events with lowest bleeding rates than therapeutic doses. In this sense, there appears to be a need for large prospective randomized clinical trials to establish the real risk-benefit of higher than prophylactic dose in critically ill COVID-19 patients. The present study has some limitations and the results must be interpreted with caution. First, this is a retrospective study, so it lacks the rigor of a prospective randomized study. Second, as it was a non-interventional study, treatment strategies were conditioned by dose group than in the prophylactic and intermediate groups (29 versus 94 and 78 respectively), limiting statistical power. Finally, we did not have reliable data on the use of aspirin and were therefore unable to include this variable in the logistic regression analysis. Our results show a significantly higher risk of bleeding and of major bleedings in patients receiving intermediate and therapeutic anticoagulant doses without a decrease in VTE events and mortality among critically ill COVID-19 patients. Moisés was involved in the conception, design of the work Aibar was involved in the conception, design of the work, critical revision of the article. All authors read, revised and approved the final manuscript. 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Gabara was involved in data collection, data analysis and interpretation and drafting the article.B. Solarat was involved in data collection and critical revision of the article. P. Castro was involved in data collection and critical revision of the article.S. Fernández was involved in data collection and critical revision of the article.J. Badia was involved in data collection and critical revision of the article. D. Toapanta was involved in data collection and critical revision of the article.