key: cord-1009206-nxpjlfk1
authors: Bellmunt, Sergi; Riera, Claudia; Gil, Daniel; Rodríguez, Manuela; García-Reyes, Marvin; Martínez-Carnovale, Lucía; Marrero, Carlos; Gil, Miquel; Ruiz, Juan Carlos; Ferrer, Ricard; de Nadal, Miriam; Monreal, Manel; Llagostera, Secundino
title: COVID-19 Infection in Critically Ill Patients Carries a High Risk for Venous Thromboembolism
date: 2020-12-23
journal: Eur J Vasc Endovasc Surg
DOI: 10.1016/j.ejvs.2020.12.015
sha: dcca26cdd37bf4dceb090156c5bab0bbde6302b4
doc_id: 1009206
cord_uid: nxpjlfk1

Objective The coronavirus disease of 2019 (COVID-19) due to SARS-CoV-2 infection has been found to cause an increased risk for venous thromboembolism (VTE). The aims of the study were to determine the frequency of VTE in critically ill patients with COVID-19 and its correlation with D-dimer levels and pharmacological prophylaxis. Methods This was a cohort study of critically ill patients due to COVID-19. All patients admitted to the intensive care unit on the same day of April 2020 were selected, regardless of length of stay, and a single bilateral venous duplex ultrasound in the lower extremities was performed up to 72 hours later. Pulmonary embolism (PE) was diagnosed with computed tomography angiography. Asymptomatic and symptomatic VTE were registered, including pre-screening in hospital VTE. Characteristics of patients, blood test results, doses of thromboprophylaxis received, VTE events, and mortality after seven day follow up were recorded. Results A total of 230 critically ill patients were studied. Median intensive care unit stay of these patients was 12 days (interquartile range [IQR] 5 – 19 days). After seven days of follow up, the frequency of patients with VTE, both symptomatic and asymptomatic, was 26.5% (95% confidence interval [CI] 21% – 32%) (69 events in 61 patients): 45 with DVT and 16 with PE (eight of them with concomitant DVT). Cumulative frequency of symptomatic VTE was 8.3% (95% CI 4.7% – 11.8%). D-dimer values ≥ 1 500 ng/mL were diagnostic for VTE, with a sensitivity of 80% and a specificity of 42%. During follow up after screening, six patients developed new VTE. Three of them developed a recurrence after a DVT diagnosed at screening, despite receiving therapeutic doses of heparin. Mortality rates at seven day follow up were the same for those with (6.6%) and without (5.3%) VTE. Conclusion Patients with severe COVID-19 infection are at high risk for VTE, and further new symptomatic VTE events and recurrence can occur despite anticoagulation. Prophylactic anticoagulation dosage may need to be increased in patients with a low risk of bleeding.

The coronavirus disease of 2019 (COVID-19) is a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), now deemed a pandemic by the World Health Organization. 1 Preliminary reports suggest that haemostatic abnormalities, including disseminated intravascular coagulation, may occur in patients infected by COVID-19. 2-4 Additionally, critical illness and immobilisation may predispose hospitalised patients with COVID-19 to develop venous thromboembolism (VTE). [5] [6] [7] In two recent studies, one in every four patients (25% and 27%) with proven COVID-19 pneumonia admitted in intensive care units (ICUs) developed symptomatic, confirmed VTE. 8, 9 In another study, 26 consecutive patients with severe COVID-19 were screened for deep vein thrombosis (DVT) by duplex ultrasound (DUS), and 69% were J o u r n a l P r e -p r o o f positive. 10 The authors suggested considering systematic screening for VTE and using high dose VTE prophylaxis in severe ICU COVID-19 patients.

It is hypothesised that a single bilateral DUS looking for DVT signs in hospitalised patients with proven COVID-19 pneumonia might detect DVT before the development of pulmonary embolism (PE). Thus, all patients were screened for DVT who had been admitted on a specific day to the ICU with COVID-19 pneumonia aimed to assess (1) the frequency of DVT and its correlation with D-dimer levels;

(2) the influence of pharmacological prophylaxis after ICU admission on the frequency of VTE; and (3) the impact on outcome of a single ultrasound screening to detect asymptomatic DVT.

This was a cohort study of patients with COVID-19 admitted to the ICUs of two The screening ultrasound was not repeated in order to avoid unnecessary exposure to the investigators due to the unknown risk of infection and, J o u r n a l P r e -p r o o f furthermore, personal protective equipment for research could not be used much at a time when it was scarce for medical staff. Exclusion criteria were a lack of confirmed diagnosis of COVID-19, current therapy with extracorporeal membrane oxygenation, pregnancy, or postpartum, and age younger than 18 years old. The protocol was approved by the Ethics Committee of Hospital Vall d'Hebron (number PR(AG)213/2020) on 6 April 2020, and due to the design of the study and the emergency created for the disease, informed consent was considered not necessary. This study was registered in Clinicaltrials.gov (NCT: 04374617). Figure 1 represents a diagram of the study design with an explanatory example. (Table 1 ). For the current study, the doses received during the 72 -96 hours prior to ultrasound scan or the symptomatic VTE events were considered, to control possible protocol deviations and to study the relationship between prophylaxis and events. In patients in whom sudden respiratory or cardiovascular deterioration occurred (mainly manifested by hypoxemia or hypotension not explained by other causes), clinical suspicion of PE was established and transthoracic echocardiography was performed. If there were signs of pulmonary hypertension, right ventricular dilatation or dysfunction, a computed tomography pulmonary angiogram (CTPA) was performed. Patients with symptomatic PE confirmed on the CTPA and those with a swollen limb and confirmed DVT on DUS were considered to have "symptomatic VTE". The remaining patients with positive DUS or CTPA were considered to have "asymptomatic VTE". "VTE frequency" for the proportion of patients with symptomatic or asymptomatic VTE detected on the day of screening, including pre-screening in hospital VTE, was considered. "VTE cumulative frequency" for the proportion of patients with symptomatic or asymptomatic VTE, including the events registered the day of the screening, pre-screening in hospital VTE and post-screening seven day follow up, was considered.

All patients with symptomatic or asymptomatic VTE were treated with therapeutic-doses of low molecular weight heparin (LMWH). All patients were followed up during the first seven days after screening. The impact of incident VTE was evaluated on mortality, risk for subsequent VTE events, and length of hospital and ICU stay. Recent studies reported a 25% rate of VTE in these patients. 8, 9 Based on this information, a sample size of 201 subjects would be sufficient to estimate this percentage of events with 95% confidence and an accuracy of ± 6% of the proportion estimate. 12 Table 2 . Most patients (80%) were on mechanical ventilation, 13% were in prone position, and 3.0% had a swollen limb. Four of the 230 patients (1.7%) had suffered a peripheral arterial thromboembolic event before being included in the study, three with acute leg ischaemia and one with acute arm ischaemia. All underwent surgery attempting to restore circulation, but one patient needed lower limb amputation.

J o u r n a l P r e -p r o o f In the seven days of follow up, there were 11 patients (4.7%) who had bleeding while being anticoagulated, five considered to be major and six nonmajor but clinically relevant. 11 Eight of these were receiving anticoagulation for J o u r n a l P r e -p r o o f related to VTE after one week than to VTE on the day of ultrasound. This is due to the fact that three patients without VTE and elevated D-dimer values on the day of the ultrasound developed VTE throughout the following week. The sensitivity was 80% (95% CI 70 -90), specificity 42% (95% CI 34 -50), positive predictive value 33% (95% CI 25 -40), negative predictive value 86% (95% CI 78 -93). The AUC value was 0.71 (95% CI 0.63 -0.78; p < .001) (Fig.   2 ).

This is the largest reported series screening for VTE in ICU patients with proven COVID-19 pneumonia and reveals a number of findings potentially useful for clinicians. First, one in every four screened patients had VTE: 23 patients had symptomatic, 38 asymptomatic VTE. Second, correlation was found between Ddimer levels at baseline and the risk for VTE. Unfortunately, a multivariable analysis could not be performed given the small simple size. Third, no influence of the LMWH dosage used for VTE prophylaxis on the frequency of VTE was found. Finally, the usefulness of a screening programme for DVT could not be confirmed in these patients since it did not prevent the development of subsequent symptomatic events.

The frequency of VTE with or without symptoms in the series was 25%, and the frequency of symptomatic VTE was 7%. In similar studies with different designs, prophylaxis, and measured outcomes, the frequency prevalence ranged between 25% and 69%. In a retrospective study on patients not receiving prophylaxis, 8 the reported incidence was 25%. In another study, 9 there was a 27% rate of symptomatic events per person time of the at risk population. Other studies found an association between raised D-dimer levels and worse prognosis. 3, 4 In one study, patients with D-dimer levels over six times the upper limit of normality had a higher mortality rate one month later among heparin users than in non-users. 4 Therefore, the authors suggested using anticoagulation in patients with markedly raised D-dimer levels. Moreover, patients with PE presented higher D-dimer levels than those with suspected but not confirmed PE. 15 Finally, D-dimer levels were found to predict VTE in a small study (81 patients), 8 with very good sensitivity and specificity. However, using the same cut-off value for D-dimer, similar sensitivity and lower specificity were obtained.

One in every two patients in the cohort (44%) was prescribed higher than standard prophylactic doses of LMWH, and this practice was not associated with a lower frequency of VTE. In the study by Llitjos et al., 9 there was a higher frequency of VTE in patients receiving standard prophylactic doses of LMWH than in those on higher doses. These differences may be explained because J o u r n a l P r e -p r o o f the protocol planned to use higher than standard prophylactic doses of LMWH only in patients with raised D-dimer levels, and it cannot ruled out that these patients might already have developed VTE. Even though other authors suggested that standard prophylactic doses may be too low, 9, 10 The study has a number of potential limitations. First, the circumstances of the pandemic made it impossible to perform a systematic screening programme throughout the whole hospital stay. As a result, only symptomatic VTE events are presented on the seventh day as it was considered inappropriate to perform repeat screening ultrasonography to detect asymptomatic DVTs. Although this might affect the validity of the study for isolated patients, the study is considered valid for this group of patients.

Second, the short follow up period and the sample size. Although ours is the largest cohort published to date on this topic, more patients are needed to J o u r n a l P r e -p r o o f develop a prognostic model and there is a need to extend the surveillance to detect further events as death, new VTE and bleeding.

In conclusion, hospitalised patients with severe COVID-19 are at high risk of VTE, despite the use of high doses of pharmacological prophylaxis in some of them. The data suggest that prophylaxis should be tailored to the patient's characteristics trying to balance the bleeding risk and clinical severity as to prescribe higher than recommended doses only in patients that would benefit most. Finally, routine ultrasound screening in a pandemic outbreak scenario did not prevent symptomatic VTE. Therefore, strict clinical surveillance is needed to detect new events that can occur despite anticoagulation.

Dr Bellmunt reports personal fees from Sanofi, personal fees from Rovi, an personal fees from Bayer, outside the submitted work. Dr Monreal reports research grants from Sanofi and Bayer during the conduct of the study. All other authors have nothing to disclose.

None. 

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Data are presented as n (%) or median (interquartile range). ICU = intensive care unit; VTE = venous thromboembolism