key: cord-0999693-55s0jct1
authors: Demelo‐Rodríguez, Pablo; Ordieres‐Ortega, Lucía; Ji, Zichen; del Toro‐Cervera, Jorge; de Miguel‐Díez, Javier; Álvarez‐Sala‐Walther, Luis A.; Galeano‐Valle, Francisco
title: Long‐term follow‐up of patients with venous thromboembolism and COVID‐19: Analysis of risk factors for death and major bleeding
date: 2021-03-03
journal: Eur J Haematol
DOI: 10.1111/ejh.13603
sha: 07ca93b0647a37b3754223b63ca285f9187a5aa1
doc_id: 999693
cord_uid: 55s0jct1

INTRODUCTION: COVID‐19 predisposes patients to a higher risk of venous thromboembolism (VTE), although the extent of these implications is unclear and the risk of bleeding has been poorly evaluated. To date, no studies have reported long‐term outcomes of patients with COVID‐19 and VTE. METHOD: Prospective observational study to evaluate long‐term (90 days or more) outcomes of patients diagnosed with VTE (PE, DVT of the extremities, or both) in the setting of COVID‐19. The main outcome of the study was a compound of major bleeding and death. RESULTS: The study comprised 100 patients (mean age 65 ± 13.9 years). At the time of VTE diagnosis, 66% patients were hospitalized, 34.8% of them in the ICU. Mean follow‐up was 97.9 ± 23.3 days. During the study period, 24% patients died and median time to death was 12 (IQR: 2.25‐20.75) days, 11% patients had major bleeding and median time to event was 12 (IQR: 5‐16) days. The cause of death was PE in 5% and bleeding in 2% of patients. There were no VTE recurrences. The main study outcome occurred in 29% patients. Risk of death or major bleeding was independently associated with ICU admission (HR 12.2; 95% CI 3.0‐48.3), thrombocytopenia (HR 4.5; 95% CI 1.2‐16.5), and cancer (HR 21.6; 95% CI 1.8‐259). CONCLUSION: In patients with COVID‐19 and VTE, mortality and major bleeding were high and almost a third of deaths were VTE‐related. The majority of complications occurred in the first 30 days. ICU admission, thrombocytopenia, and cancer are risk factors for poor prognosis.

Venous thromboembolism (VTE) includes deep vein thrombosis (DVT) and pulmonary embolism (PE). It causes more than 250 000 hospital admissions per year, with an incidence of 104-183 cases per 100 000 inhabitants per year. It also entails an elevated risk of morbimortality, including VTE recurrence, bleeding, and early mortality, which can reach up to 40% at 10 years. 1, 2 Since December 2019, a viral respiratory illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19, has spread throughout the world and was declared a pandemic on March 2020. 3 This disease has been reported to potentially predispose patients to a higher risk of VTE, although the extent of these implications is not yet clear. 4 Many possible explanations have been suggested, including generalized inflammatory response, endothelial dysfunction, 5 immobilization, and disseminated intravascular coagulation (DIC). 6 Due to these alterations, thromboprophylaxis is recommended for admitted COVID-19 patients and appears to be associated with a lower mortality rate. 6, 7 In patients admitted in Intensive Care Unit (ICU), a higher risk of VTE, despite proper thromboprophylaxis, has been reported. 8 Nonetheless, when VTE is diagnosed, patients should undergo anticoagulation at therapeutic doses if there are no contraindications, according to the current available guidelines. 9 The risk of bleeding should always be considered in patients under anticoagulation, especially in COVID-19 patients, since there is still scarce available evidence. A recent study found an overall risk of bleeding of 4.8% in COVID-19 patients. 10 To date, no studies have reported long-term outcomes of patients with COVID-19 and VTE. The objective of our study is to describe the long-term outcomes of COVID-19 patients with VTE and to analyze the risk factors of poor prognosis.

Prospective observational study performed in a tertiary hospital in Madrid to evaluate the long-term (90 days or more) outcomes of patients diagnosed with VTE in the setting of SARS-CoV-2 infection.

The investigators did not receive funds for the present study. 

Patients were followed up for a minimum of 90 days or until fatal outcome occurred.

The baseline data of the patients were collected including epidemiological data, characteristics of the VTE episode, diagnosis of COVID-19, complementary tests and treatment received. The main outcome of the study was a compound of major bleeding and death.

Major bleeding was classified according to the ISTH guidelines including as follows: fatal bleeding; bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome; bleeding leading to transfusion of two or more units of whole blood or red cells. Patients with PE were classified according to the ESC (European Society of Cardiology) risk score. 11 of means in 2 categories and in several independent categories, respectively, when the distribution is non-parametric. The Kaplan-Meier estimator is used to graphically represent the events (death, hemorrhage, and recurrence). In 91% of patients, there was at least one provoking factor for VTE besides COVID-19 itself, with 11% patients with more than one provoking factor (Table 1) . Anemia, lymphopenia, and elevated Ddimer were the most common laboratory findings in these patients (Table 1) . During the acute phase (first 10 days), most patients received low molecular weight heparin (LMWH) or unfractionated heparin; 7% received fibrinolytics; and only 1 patient required inferior vena cava filter placement. Long-term therapy of choice was direct oral anticoagulants (DOACs) in 52% of patients, followed by LMWH in 28% patients. Treatment strategies are detailed in Table 2 .

Median follow-up was 97 (IQR 89, 111) days. During the study period, 24 patients died (24.0%), 20 patients bled (20%) and there were no VTE recurrences. PE was the cause of death in 5 patients (20.5%); 2 patients died due to bleeding (8.3%), and 15 patients died of respiratory failure due to COVID-19 (62.5%) ( Table 3) Table 3 .

We analyzed the predictive capacity of the ESC classification for mortality in PE patients. Mortality was significantly higher in patients in the high-risk group when compared with the intermediate and low-risk groups (100% vs 23.1% vs 15.6%, P < .001). We also studied the predictive capacity of RIETE score and HAS-BLED score to predict major bleeding, with no significant differences between them (P = .51 for RIETE score and P = .78 for HAS-BLED score).

The main study outcome (a compound of death and major bleeding) was observed in 29 patients (29.0%). The development of main outcome was significantly associated with ICU admission, anemia, thrombocytopenia, and cancer ( decisions to test and diagnose VTE. A second limitation is that in the absence of an independent adjudication committee or autopsy;

this study cannot provide information on the specific contribution of VTE to the mortality rate that we observed among patients who required hospitalization for COVID-19. Third, the absence of a control group (COVID-19 patients without VTE) limits the conclusions that can be drawn. Finally, as stated earlier, it must be clarified that the current study did not focus on the comparative effectiveness of strategies for VTE prevention or treatment. Results from ongoing randomized trials will be much more informative for that purpose.

In conclusion, in patients with COVID-19 and VTE, mortality, and major bleeding were high and almost a third of deaths were VTErelated. The majority of complications occurred in the first 30 days.

ICU admission, thrombocytopenia, and cancer are risk factors for poor prognosis.

None to declare. 

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