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SARS-CoV-2 infection and venous thromboembolism after surgery: an international prospective cohort study

Summary SARS-CoV-2 has been associated with an increased rate of venous thromboembolism in critically ill patients. Since surgical patients are already at higher risk of venous thromboembolism than general populations, this study aimed to determine if patients with peri-operative or prior SARS-CoV-2 were at further increased risk of venous thromboembolism. We conducted a planned sub-study and analysis from an international, multicentre, prospective cohort study of elective and emergency patients undergoing surgery during October 2020. Patients from all surgical specialties were included. The primary outcome measure was venous thromboembolism (pulmonary embolism or deep vein thrombosis) within 30 days of surgery. SARS-CoV-2 diagnosis was de ﬁ ned as peri-operative (7 days before to 30 days after surgery); recent (1 – 6 weeks before surgery); previous ( ≥ 7 weeks before surgery); or none. Information on prophylaxis regimens or pre-operative anti-coagulation for baseline comorbidities was not available. Postoperative venous thromboembolism rate was 0.5% (666/123,591) in patients without SARS-CoV-2; 2.2% (50/2317) in patients with peri-operative SARS-CoV-2; 1.6% (15/953) in patients with recent SARS-CoV-2; and 1.0% (11/1148) in patients with previous SARS-CoV-2. After adjustment for confounding factors, patients with peri-operative (adjusted odds ratio 1.5 (95%CI 1.1 – 2.0)) and recent SARS-CoV-2 (1.9 (95%CI 1.2 – 3.3)) remained at higher risk of venous thromboembolism, with a borderline ﬁ nding in previous SARS-CoV-2 (1.7 (95%CI 0.9 – 3.0)). Overall, venous thromboembolism was independently associated with 30-day mortality (5.4 (95%CI 4.3 – 6.7)). In patients with SARS-CoV-2, mortality without venous thromboembolism was 7.4% (319/4342) and with venous thromboembolism was 40.8% (31/76). Patients undergoing surgery with peri-operative or recent SARS-CoV-2 appear to be at increased risk of postoperative venous thromboembolism compared with patients with no history of SARS-CoV-2 infection. Optimal venous thromboembolism prophylaxis and treatment are unknown in this cohort of patients, and these data should be interpreted accordingly.


Introduction
Patients hospitalised with COVID-19 have a high risk of venous thromboembolism (VTE), with an estimated incidence between 9% and 26% [1-5] despite pharmacological prophylaxis, and as high as 21-31% in patients within critical care settings [1,2,4,6]. As a result, preliminary mixed guidance has been issued, with some suggesting no change in practice, while others suggesting that increased doses and duration of pharmacological prophylaxis may be beneficial [7,8]. However, such 28 regimens are associated with serious bleeding risks [9].

Methods
This study was conducted according to guidelines set by the strengthening the reporting of observational studies in epidemiology (STROBE) statement for observational studies [11]. This was a planned sub-study and analysis from a prospective, international, multicentre cohort study of patients undergoing surgery during October 2020. Data were collected as part of this larger study in the same time frame. This prior study focused on overall 30-day mortality with specific reporting on pulmonary complications. The methods and findings of this study were published previously [12].
Hospitals providing surgery from any surgical specialty were eligible for participation. Study approvals for participating hospitals were secured in line with local and national regulations before entry into the study. Local investigators were required to confirm that all mandatory approvals were in place before data collection could begin.
The study protocol was either registered as a clinical audit with institutional review or a research study obtaining ethical committee approval depending on local and national requirements. Informed patient consent was obtained if this was necessary to comply with local or national regulations. In the UK, this study was registered as a clinical audit in the central co-ordinating site and registered as either an audit or service evaluation at other recruiting institutions. Therefore, consent was not mandated from individual patients. Data were collected online and stored on a secure server running the Research Electronic Data Capture (REDCap, Vanderbilt University, Nashville, TN, USA) web application [13], based at the University of Birmingham, UK. Hospitals registered their interest to participate based on one or more surgical specialties.
Participating specialties then collected data on consecutive patients who underwent surgery within their department during one or more pre-selected weeks between 5 October and 1 November 2020, with a 30-day postoperative followup period. No changes were made to local patient care protocols during the course of this study. Only anonymised, routine clinical data were collected.
Adult patients, aged 18 y and over, undergoing elective or emergency surgery for any indication, from any specialty, were eligible. As VTE events are very rare in patients aged <18 y, these patients were not included from this current analysis. Surgery was defined as any procedure routinely performed in an operating theatre by a surgeon. A list of excluded procedures can be found in online Supporting Information Table S1.
Baseline patient characteristics included age, ASA physical status and smoking status. Age was collected as a categorical variable in deciles of years and categorised into three groups for analysis: 18-49 y; 50-69 y; and ≥70 y. The ASA physical status was dichotomised to 1-2 or 3-5.
Patients were identified as smokers if they were current smokers or had smoked in the six weeks before surgery.
Data collected on pre-existing medical conditions included respiratory comorbidities (asthma; chronic obstructive pulmonary disease); congestive cardiac failure; cerebrovascular disease; chronic kidney disease; and ischaemic heart disease. Indications for surgery were classified as: benign disease; cancer; obstetrics; or trauma. Operative variables included urgency of surgery (elective or emergency); type of anaesthesia (local/regional or general); and grade of surgery (minor or major). National income was based on the World Bank's classification for each participating country [14].

Results
This analysis included 128,013 patients, from 1630 hospitals across 115 countries. Baseline patient and operative  In patients with pre-operative SARS-CoV-2 infection, the presence of ongoing SARS-CoV-2 symptoms was associated with increased incidence of VTE when compared with patients without ongoing symptoms (Fig. 4). Ongoing symptoms were associated with an overall 4.6% (17/406) rate of postoperative VTE vs. 0.8% (21/2547) in patients who were asymptomatic or whose symptoms had resolved. This effect persisted even after stratifying patients by timing of SARS-CoV-2 diagnosis (Fig. 4) and was observed even in symptomatic patients with a SARS-CoV-2 diagnosis  0.7% in asymptomatic or resolved patients).
Overall, the rate of 30-day postoperative mortality was 1.7% (2195/128,009). When this was stratified by SARS-

Discussion
This planned sub-study found that SARS-CoV-2 infection was independently associated with an increased incidence

Supporting Information
Additional supporting information may be found online via the journal website.
Appendix S2. Definitions of terms used in this study.
Tables S1. List of excluded procedures. Tables S6. Adjusted sub-group analysis for VTE in major surgery patients only.
Tables S7. Adjusted sub-group analysis for VTE in minor surgery patients only.