Anaesthesia 2021 doi:10.1111/anae.15563 Original Article SARS-CoV-2 infection and venous thromboembolism after surgery: an international prospective cohort study COVIDSurg Collaborative* and GlobalSurg Collaborative* NIHR Global Health Research Unit on Global Surgery, Birmingham, UK 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 defined 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 finding 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. ................................................................................................................................................................. Correspondence to: E. Li Email: elizabeth.li@nhs.net Accepted: 20 July 2021 Keywords: COVID-19; deep vein thrombosis; pulmonary embolism; SARS-CoV-2; venous thromboembolism *Collaborating authors are listed in online Supporting Information Appendix S1. Twitter: @CovidSurg; @GlobalSurg Introduction patients within critical care settings [1, 2, 4, 6]. As a result, Patients hospitalised with COVID-19 have a high risk of preliminary mixed guidance has been issued, with some venous thromboembolism (VTE), with an estimated suggesting no change in practice, while others suggesting incidence between 9% and 26% [1–5] despite that increased doses and duration of pharmacological pharmacological prophylaxis, and as high as 21–31% in prophylaxis may be beneficial [7, 8]. However, such © 2021 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists. 1 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Anaesthesia 2021 COVIDSurg Collaborative and GlobalSurg Collaborative | SARS-CoV-2 infection and venous thromboembolism after surgery regimens are associated with serious bleeding risks [9]. institutions. Therefore, consent was not mandated from Determining the optimal VTE prophylactic regimen for individual patients. Data were collected online and stored patients with moderate and severe COVID-19 is an active on a secure server running the Research Electronic Data area of research (e.g. REMAP-CAP, ACTIV-4a, ATTACC Capture (REDCap, Vanderbilt University, Nashville, TN, Investigators, pre-print, https://doi.org/10.1101/2021.03. USA) web application [13], based at the University of 10.21252749) [10]. Birmingham, UK. Hospitals registered their interest to The incidence of VTE in surgical patients infected with participate based on one or more surgical specialties. SARS-CoV-2 is not well known. Most patients undergoing Participating specialties then collected data on consecutive surgery already have risk-factors for VTE, including patients who underwent surgery within their department immobility, surgical wounds and systematic inflammation. during one or more pre-selected weeks between 5 October The addition of SARS-CoV-2 infection may further increase and 1 November 2020, with a 30-day postoperative follow- this risk, but the extent and impact are unknown, and large up period. No changes were made to local patient care scale, prospective patient-level data are lacking. Surgical protocols during the course of this study. Only anonymised, patients may also carry asymptomatic SARS-CoV-2 routine clinical data were collected. infections, and whether this contributes to excess risk is also Adult patients, aged 18 y and over, undergoing unknown. elective or emergency surgery for any indication, from any Robust evidence is needed to enable clinicians and specialty, were eligible. As VTE events are very rare in policymakers to minimise VTE risk in patients with SARS- patients aged <18 y, these patients were not included from CoV-2 infection. Ideally, such evidence would stratify the risk this current analysis. Surgery was defined as any procedure of VTE against both the duration of time between infection routinely performed in an operating theatre by a surgeon. A and surgery and presence or absence of symptoms. This list of excluded procedures can be found in online study aimed to determine the VTE rate in patients with Supporting Information Table S1. SARS-CoV-2 infection, stratified by current or prior infection. Baseline patient characteristics included age, ASA physical status and smoking status. Age was collected as a Methods categorical variable in deciles of years and categorised into This study was conducted according to guidelines set by the three groups for analysis: 18–49 y; 50–69 y; and ≥70 y. The strengthening the reporting of observational studies in ASA physical status was dichotomised to 1–2 or 3–5. epidemiology (STROBE) statement for observational Patients were identified as smokers if they were current studies [11]. This was a planned sub-study and analysis from smokers or had smoked in the six weeks before surgery. a prospective, international, multicentre cohort study of Data collected on pre-existing medical conditions included patients undergoing surgery during October 2020. Data respiratory comorbidities (asthma; chronic obstructive were collected as part of this larger study in the same time pulmonary disease); congestive cardiac failure; cerebro- frame. This prior study focused on overall 30-day mortality vascular disease; chronic kidney disease; and ischaemic with specific reporting on pulmonary complications. The heart disease. Indications for surgery were classified as: methods and findings of this study were published benign disease; cancer; obstetrics; or trauma. Operative previously [12]. variables included urgency of surgery (elective or Hospitals providing surgery from any surgical specialty emergency); type of anaesthesia (local/regional or general); were eligible for participation. Study approvals for and grade of surgery (minor or major). National income was participating hospitals were secured in line with local and based on the World Bank’s classification for each national regulations before entry into the study. Local participating country [14]. investigators were required to confirm that all mandatory A positive SARS-CoV-2 diagnosis was based on a approvals were in place before data collection could begin. patient having one or more of the following: a positive The study protocol was either registered as a clinical audit reverse transcriptase-polymerase chain reaction (RT-PCR) with institutional review or a research study obtaining nasopharyngeal swab; a positive rapid antigen test; chest ethical committee approval depending on local and computed tomography (CT) scan showing changes in national requirements. Informed patient consent was keeping with locally implemented protocols that indicate obtained if this was necessary to comply with local or SARS-CoV-2 infection; positive immunoglobulin G or national regulations. In the UK, this study was registered as a immunoglobulin M antibody test; or clinical diagnosis of clinical audit in the central co-ordinating site and registered symptoms in keeping with COVID-19 in patients where no as either an audit or service evaluation at other recruiting swab test or CT scan were available. Timing of diagnosis of 2 © 2021 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists. COVIDSurg Collaborative and GlobalSurg Collaborative | SARS-CoV-2 infection and venous thromboembolism after surgery Anaesthesia 2021 Table 1 Baseline patient, disease and operative characteristics stratified by SARS-CoV-2 status. Values are number (proportion). No SARS-CoV-2 Peri-operative SARS-CoV-2 Recent SARS-CoV-2 Previous SARS-CoV-2 p value n = 123,595 n = 2317 n = 953 n = 1148 Age; y 18–49 55,651 (45.0%) 968 (41.8%) 461 (48.4%) 480 (41.8%) <0.001 50–69 41,633 (33.7%) 696 (30.0%) 332 (34.8%) 470 (40.9%) ≥70 26,309 (21.3%) 653 (28.2%) 160 (16.8%) 198 (17.3%) Missing 2 0 0 0 Sex Female 66,495 (53.8%) 1228 (53.0%) 493 (51.7%) 611 (53.2%) 0.506 Male 57,096 (46.2%) 1089 (47.0%) 460 (48.3%) 537 (46.8%) Missing 4 0 0 0 ASA physical status 1–2 91,229 (73.8%) 1399 (60.4%) 635 (66.6%) 759 (66.1%) <0.001 3–5 32,323 (26.2%) 918 (39.6%) 318 (33.4%) 389 (33.9%) Missing 43 0 0 0 Smoking No 103,387 (83.9%) 1949 (84.3%) 845 (88.9%) 1017 (88.8%) <0.001 Yes 19,835 (16.1%) 364 (15.7%) 106 (11.1%) 128 (11.2%) Missing 373 4 2 3 Respiratory comorbidity No 111,785 (90.5%) 2026 (87.5%) 854 (89.6%) 1027 (89.5%) <0.001 Yes 11,713 (9.5%) 290 (12.5%) 99 (10.4%) 121 (10.5%) Missing 97 1 0 0 Congestive heart failure No 118,829 (96.2%) 2151 (92.8%) 907 (95.2%) 1079 (94.0%) <0.001 Yes 4738 (3.8%) 166 (7.2%) 46 (4.8%) 69 (6.0%) Missing 28 0 0 0 Cerebral vascular disease No 119,253 (96.5%) 2190 (94.5%) 922 (96.7%) 1103 (96.1%) <0.001 Yes 4314 (3.5%) 127 (5.5%) 31 (3.3%) 45 (3.9%) Missing 28 0 0 0 Chronic kidney disease No 120,475 (97.5%) 2179 (94.0%) 900 (94.4%) 1094 (95.3%) <0.001 Yes 3092 (2.5%) 138 (6.0%) 53 (5.6%) 54 (4.7%) Missing 28 0 0 0 Ischaemic heart disease No 112,894 (91.4%) 1995 (86.1%) 856 (89.8%) 1037 (90.3%) <0.001 Yes 10,673 (8.6%) 322 (13.9%) 97 (10.2%) 111 (9.7%) Missing 28 0 0 0 Indication Benign disease 76,169 (61.6%) 1215 (52.4%) 561 (58.9%) 777 (67.7%) <0.001 Malignancy 23,251 (18.8%) 421 (18.2%) 211 (22.1%) 231 (20.1%) Trauma 14,595 (11.8%) 436 (18.8%) 114 (12.0%) 91 (7.9%) Obstetric 9577 (7.8%) 245 (10.6%) 67 (7.0%) 49 (4.3%) Missing 3 0 0 0 (continued) © 2021 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists. 3 Anaesthesia 2021 COVIDSurg Collaborative and GlobalSurg Collaborative | SARS-CoV-2 infection and venous thromboembolism after surgery Table 1 (continued) No SARS-CoV-2 Peri-operative SARS-CoV-2 Recent SARS-CoV-2 Previous SARS-CoV-2 p value n = 123,595 n = 2317 n = 953 n = 1148 Grade of surgery Minor 47,178 (38.2%) 695 (30.0%) 285 (29.9%) 439 (38.2%) <0.001 Major 76,392 (61.8%) 1622 (70.0%) 668 (70.1%) 709 (61.8%) Missing 25 0 0 0 Urgency of surgery Elective 87,117 (70.5%) 965 (41.6%) 604 (63.4%) 857 (74.7%) <0.001 Emergency 36,471 (29.5%) 1352 (58.4%) 349 (36.6%) 291 (25.3%) Missing 7 0 0 0 Anaesthesia Local/regional 34,508 (27.9%) 707 (30.5%) 222 (23.3%) 285 (24.8%) <0.001 General 89,035 (72.1%) 1609 (69.5%) 731 (76.7%) 863 (75.2%) Missing 52 1 0 0 Country income High 20,624 (66.9%) 399 (55.3%) 242 (38.4%) 121 (58.8%) <0.001 Upper middle 20,238 (16.4%) 636 (27.4%) 345 (36.2%) 352 (30.7%) Low middle/low 82,733 (16.7%) 1282 (17.2%) 366 (25.4%) 675 (10.5%) Missing 0 0 0 0 SARS-CoV-2 in relation to the day of surgery was collected Patients with data missing on VTE or SARS-CoV-2 status as a categorical variable and further collapsed into one of and patients aged <18 y were excluded in the analysis. The the following groups for analysis: no SARS-CoV-2; peri- Chi-square test of independence was used to compare operative SARS-CoV-2 (diagnosed 7 days before to 30 days groups in terms of categorical data. For the primary after surgery); recent SARS-CoV-2 (diagnosed 1–6 weeks outcome of VTE within 30 days of surgery, multivariable before surgery); or previous SARS-CoV-2 (diagnosed logistic regression analysis was used to evaluate the ≥7 weeks before surgery). Data were also collected on the association of SARS-CoV-2 infection and VTE after surgery, presence or absence of respiratory or non-respiratory SARS- which was summarised using OR (95%CI). The model CoV-2 symptoms if patients had a pre-operative SARS-CoV- included clinically relevant patient and operative factors in 2 diagnosis. These were analysed as a combined group of order to adjust for covariates and reduce the risk of patients with asymptomatic infection or those with previous confounding (baseline patient characteristics; pre-existing symptoms now resolved, or patients with ongoing comorbidities; operative factors). Multivariable adjusted symptoms. Symptoms in patients with a postoperative sub-group analyses were performed based on the main SARS-CoV-2 diagnosis were not analysed as it was not analysis to define the patients in which SARS-CoV-2 possible to separate these from standard postoperative infection was associated with additional risk of symptoms. postoperative VTE above the expected baseline risk of that The primary outcome measure was VTE within 30 days sub-group. This was done in the following four sub-groups: following surgery. Venous thromboembolism was defined major surgery; minor surgery; elective surgery; and as either deep vein thrombosis (DVT) or pulmonary emergency surgery. A multivariable adjusted analysis was embolism (PE). Deep vein thrombosis was defined as lower also fitted for 30-day mortality as the outcome with VTE as limb DVT with or without symptoms that was proven the main explanatory variable, using clinically relevant radiologically; and PE was defined as symptomatic PE, patient and operative factors for adjustment. Analyses were radiologically proven or fatal PE discovered at post-mortem performed with Stata SE version 16.1, (StataCorp, TX, USA). or as judged by the clinical team. Secondary outcome measures were postoperative pneumonia and mortality Results within 30 days of surgery. Full study definitions can be This analysis included 128,013 patients, from 1630 hospitals found in online Supporting Information Appendix S2. across 115 countries. Baseline patient and operative 4 © 2021 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists. COVIDSurg Collaborative and GlobalSurg Collaborative | SARS-CoV-2 infection and venous thromboembolism after surgery Anaesthesia 2021 Figure 1 Flow diagram of patients showing venous thromboembolism (VTE), pneumonia, mortality and SARS-CoV-2 infection. characteristics are shown in Table 1. Of these patients, vs. 21.3%, p < 0.001), ASA physical status 3–5 (39.6% vs. 59,182 (46.2%) were men; 94,022 (73.5%) were ASA 26.2%, p < 0.001), underwent emergency surgery more physical status 1–2 and 20,433 (16.0%) were smokers. The often (58.4% vs. 29.5%, p < 0.001) and had a greater total number of patients who had a diagnosis of SARS-CoV- comorbid burden (Table 1). This trend was also present 2 infection was 4418 (3.5%). The timing of SARS-CoV-2 when comparing patients without SARS-CoV-2 and those diagnosis in relation to the day of surgery was peri- with recent and previous infection (Table 1). operative (7 days before to 30 days after surgery) for 2317 Overall, the rate of postoperative VTE was 0.6% (742/ patients (1.8%); recent (1–6 weeks before surgery) for 953 128,013). Of these 742 patients, 44.3% (329) had a PE only, patients (0.7%); and previous (≥7 weeks before surgery) for 47.5% (352) had a DVT only and 8.2% (61) had both. A full 1148 patients (0.9%; Fig. 1). Postoperative pneumonia was description of the VTE event rates in relation to patient and chosen as the best fitting variable to represent more severe operative characteristics are reported in Table 2 and details SARS-CoV-2 infection. Proportionally, pneumonia occurred of PE and DVT by specialty can be found in online most frequently in patients with peri-operative SARS-CoV-2 Supporting Information Table S2. In adjusted analyses, (497 patients, 21.5%), followed by recent SARS-CoV-2 significant predictors of postoperative VTE were peri- patients (73, 7.7%). Patients with previous SARS-CoV-2 (19, operative and recent SARS-CoV-2 infection; pneumonia; 1.7%) and no SARS-CoV-2 diagnosis (2083, 1.7%) had the age >50 y; ASA physical status 3–5; chronic kidney disease; same risk for postoperative pneumonia (Fig. 1). Compared surgery for malignancy or trauma; major surgery; with patients who did not have SARS-CoV-2 infection, emergency surgery; having a general anaesthetic; and patients with peri-operative SARS-CoV-2 were older (28.2% surgery performed in a country of upper-middle, low- © 2021 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists. 5 Anaesthesia 2021 COVIDSurg Collaborative and GlobalSurg Collaborative | SARS-CoV-2 infection and venous thromboembolism after surgery Table 2 Unadjusted venous thromboembolism (VTE) rates Table 2 (continued) by patient, disease and operative factors. Values are number (proportion). No VTE VTE n = 127,270 n = 742 p value No VTE VTE n = 127,270 n = 742 p value Grade of surgery Minor 48,465 (38.1%) 132 (17.8%) <0.001 Age; y Major 78,781 (61.9%) 610 (82.2%) 18–49 57,368 (45.1%) 192 (25.9%) <0.001 Missing 25 50–69 42,852 (33.7%) 279 (37.6%) Urgency of surgery ≥70 27,049 (21.3%) 271 (36.5%) Elective 89,192 (70.1%) 351 (47.3%) <0.001 Missing 2 0 Emergency 38072 (29.9%) 391 (52.7%) Sex Missing 7 Female 68,447 (53.8%) 380 (51.2%) 0.161 Anaesthesia Male 58,820 (46.2%) 362 (48.8%) Regional/local 35,597 (28.0%) 125 (16.8%) <0.001 Missing 4 0 General 91,650 (72.0%) 617 (83.2%) ASA physical status Missing 53 1–2 93,699 (73.7%) 323 (43.5%) <0.001 Country income 3–5 33,529 (26.3%) 419 (56.5%) High 84,572 (66.4%) 484 (65.2%) 0.268 Missing 43 0 Upper middle 21,453 (16.9%) 118 (15.9%) Smoking Low middle/low 21,246 (16.7%) 140 (18.9%) No 106,582 (84.0%) 616 (83.2%) 0.578 Missing 0 Yes 20,309 (16.0%) 124 (16.8%) Missing 380 2 Respiratory comorbidity No 115,067 (90.5%) 625 (84.2%) <0.001 middle or low income (Fig. 2, detailed in online Supporting Yes 12,106 (9.5%) 117 (15.8%) Information Table S3). Pneumonia was strongly associated Missing 98 with postoperative VTE, and obstetric procedures had a Congestive heart failure lower rate of VTE when compared with benign (non- No 122,296 (96.1%) 670 (90.3%) <0.001 obstetric, non-cancer) surgery (Fig. 2). Yes 4947 (3.9%) 72 (9.7%) When compared against the main adjusted analysis Missing 28 0 of all patients (Fig. 2), sub-group analysis of elective Cerebral vascular disease surgery patients only demonstrated a stronger association No 122,786 (96.5%) 682 (91.9%) <0.001 between peri-operative and recent SARS-CoV-2 infection Yes 4457 (3.5%) 60 (8.1%) and VTE; this effect was diminished in patients having Missing 28 0 emergency surgery (Fig. 3). Sub-group analysis in major Chronic kidney disease surgery demonstrated similar risk of postoperative VTE to No 123,962 (97.4%) 686 (92.5%) <0.001 the main analysis in patients with peri-operative, recent or Yes 3281 (2.6%) 56 (7.5%) previous SARS-CoV-2 infection, although there was no Missing 28 0 significant effect in patients who had minor surgery Ischaemic heart disease (Fig. 3). No 116,174 (91.3%) 608 (81.9%) < 0.001 In patients with pre-operative SARS-CoV-2 infection, Yes 11069 (8.7%) 134 (18.1%) the presence of ongoing SARS-CoV-2 symptoms was Missing 28 associated with increased incidence of VTE when compared Indication with patients without ongoing symptoms (Fig. 4). Ongoing Benign disease 78,373 (61.6%) 349 (47.0%) <0.001 symptoms were associated with an overall 4.6% (17/406) Malignancy 23,915 (18.8%) 199 (26.8%) rate of postoperative VTE vs. 0.8% (21/2547) in patients who Trauma 15,066 (11.8%) 170 (22.9%) were asymptomatic or whose symptoms had resolved. This Obstetric 9914 (7.8%) 24 (3.2%) effect persisted even after stratifying patients by timing of Missing 3 SARS-CoV-2 diagnosis (Fig. 4) and was observed even in symptomatic patients with a SARS-CoV-2 diagnosis (continued) 6 © 2021 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists. COVIDSurg Collaborative and GlobalSurg Collaborative | SARS-CoV-2 infection and venous thromboembolism after surgery Anaesthesia 2021 ≥7 weeks before surgery (5.7% in symptomatic patients vs. adjusted analyses, VTE was independently and strongly 0.7% in asymptomatic or resolved patients). associated (OR 5.4 (95%CI 4.4–6.8)) with 30-day mortality Overall, the rate of 30-day postoperative mortality was (Table 4). 1.7% (2195/128,009). When this was stratified by SARS- CoV-2 infection and postoperative VTE, unadjusted Discussion analyses demonstrated an incremental increase in mortality This planned sub-study found that SARS-CoV-2 infection rates with SARS-CoV-2 infection and VTE (Table 3). In was independently associated with an increased incidence SARS-CoV-2 status No SARS Ref peri-op SARS 1.48 (1.08–2.03) 1–6 weeks SARS 1.96 (1.16–3.33) ≥ 7 weeks 1.66 (0.90–3.04) Pneumonia No Ref Yes 3.73 (2.98–4.68) Age 18–49 years Ref 50–69 years 1.50 (1.22–1.84) 70+ 1.68 (1.34–2.12) Sex Female Ref Male 0.88 (0.76–1.03) ASA Grade 1–2 Ref Grade 3–5 2.03 (1.70–2.42) Smoker No Ref Yes 1.06 (0.87–1.30) Respiratory comorbidities No Ref Yes 1.15 (0.93–1.42) Congestive heart failure No Ref Yes 1.16 (0.89–1.51) Cerebral vascular disease No Ref Yes 1.15 (0.87–1.52) Chronic Kidney disease No Ref Yes 1.49 (1.12–1.99) Ischemic heart disease No Ref Yes 1.08 (0.88–1.33) Indication Benign Ref Malignancy 1.70 (1.41–2.05) Trauma 1.59 (1.29–1.95) Obstetric 0.62 (0.38–1.00) Grade Minor Ref Major 1.96 (1.61–2.40) Urgency Elective Ref Emergency 2.35 (1.98–2.79) Anaesthetic Local / regional Ref General 1.47 (1.19–1.83) Country income High Ref Upper middle 1.20 (0.97–1.48) Lower middle/low 1.78 (1.45–2.19) 0 1 2 3 4 5 Figure 2 Forest plot of adjusted regression model for factors associated with venous thromboembolism. Figures show the reference value (Ref) and OR (95%CI) for the levels of each variable. © 2021 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists. 7 Anaesthesia 2021 COVIDSurg Collaborative and GlobalSurg Collaborative | SARS-CoV-2 infection and venous thromboembolism after surgery of postoperative VTE in patients with peri-operative and Overall, emergency surgery patients have a higher rate recent SARS-CoV-2 infection. In patients with pre-operative of postoperative VTE. However, sub-group analysis SARS-CoV-2, ongoing symptoms were associated with an demonstrated that in elective patients, there was a greater increased rate of postoperative VTE, irrespective of how additional VTE risk in patients with SARS-CoV-2 when long before surgery the diagnosis was made. Pneumonia compared with patients with no SARS-CoV-2. This was strongly associated with postoperative VTE, possibly additional risk was not as pronounced in emergency due to a combination of SARS-CoV-2-induced pneumonitis surgery patients. Without data on any differences in the VTE and a more difficult postoperative period involving prophylaxis and anticoagulation regimes between the infection, increased disease burden and greater immobility. elective and emergency surgery patients, no firm Mortality was highest in patients with SARS-CoV-2 infection conclusions can be drawn. However, it is possible that this and VTE, and in adjusted analyses, SARS-CoV-2 and VTE could be a consequence of the greater number of VTE risk- were both independently associated with 30-day mortality. factors associated with emergency surgery, resulting in any However, these results were limited by a lack of information additional risk from SARS-CoV-2 infection having less of an on pre-operative anticoagulant use and postoperative VTE impact on the overall risk of postoperative VTE. This prophylactic regimens. translates into a disproportionately increased risk in patients Odds ratio (95% CI) (a) Elective No SARS-CoV-2 Ref Peri-operative SARS-CoV-2 2.10 (1.27–3.48) Recent (1–6 weeks) SARS-CoV-2 2.93 (1.52–5.64) Previous (≥ 7 weeks) SARS-CoV-2 1.51 (0.62–3.68) Emergency No SARS-CoV-2 Ref Peri-operative SARS-CoV-2 1.26 (0.84–1.88) Recent (1–6 weeks) SARS-CoV-2 1.15 (0.47–2.84) Previous (≥ 7 weeks) SARS-CoV-2 1.85 (0.81–4.24) 0 1 2 3 4 5 6 Odds ratio (b) (95% CI) Major No SARS-CoV-2 Ref Peri-operative SARS-CoV-2 1.55 (1.10–2.18) Recent (1–6 weeks) SARS-CoV-2 1.92 (1.07–3.46) Previous (≥ 7 weeks) SARS-CoV-2 2.04 (1.11–3.75) Minor No SARS-CoV-2 Ref Peri-operative SARS-CoV-2 1.10 (0.48–2.48) Recent (1–6 weeks) SARS-CoV-2 1.69 (0.50–5.72) Previous (≥ 7 weeks) SARS-CoV-2 No observations 0 1 2 3 4 5 6 Figure 3 Adjusted sub-group analysis for venous thromboembolism in (A) elective and emergency patients and (B) major and minor surgery patients. Sub-group analyses are adjusted for the following variables: pneumonia; age; sex; ASA physical status; smoker; respiratory comorbidities; congestive heart failure; cerebral vascular disease; chronic kidney disease; ischaemic heart disease; indication; grade; urgency; anaesthesia; and country income. Full details can be found in online Supporting Information Tables S4 to S7. Figures show the reference value (Ref) and OR (95%CI) for the levels of each variable. 8 © 2021 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists. COVIDSurg Collaborative and GlobalSurg Collaborative | SARS-CoV-2 infection and venous thromboembolism after surgery Anaesthesia 2021 Figure 4 Venous thromboembolism (VTE) and 30-day mortality in patients with pre-operative SARS-CoV-2 by presence or absence of COVID-19 symptoms. Table 3 Rate of 30-day mortality stratified by SARS-CoV-2 and venous thromboembolism (VTE) status. Values are fraction (proportion) No VTE VTE p value All patients 2047/127,271 1.6% 148/742 20.0% < 0.001 No SARS-CoV-2 infection 1728/122,929 1.4% 117/666 17.6% < 0.001 Any SARS-CoV-2 infection 319/4342 7.4% 31/76 40.8% < 0.001 Peri-operative SARS-CoV-2 236/2267 10.4% 20/50 40.0% < 0.001 Recent SARS-CoV-2 60/938 6.4% 10/15 66.7% < 0.001 Previous SARS-CoV-2 23/1137 2.0% 1/11 9.1% 0.103 undergoing elective surgery. Sub-group analysis also However, improved outcomes and a reduced requirement demonstrated greater additional risk in patients for organ support has been seen in patients with moderate undergoing major surgery. This is most likely due to the severity of COVID-19 (i.e. hospitalised) who receive smaller proportion of patients with peri-operative SARS- therapeutic anticoagulation [15]. This highlights the CoV-2 infection having minor elective surgery during the challenge of anticoagulating patients with COVID-19, which ongoing pandemic. Overall, minor surgery patients were is likely to be even more complex in patients having surgery, exposed to fewer of the risk-factors for VTE, and baseline although our results suggest that anticoagulation in patients VTE rate was low. Concurrent SARS-CoV-2 infection was not with previous, recent or peri-operative SARS-CoV-2 associated with a significant increase in additional risk. infection may be an important consideration. There have been numerous studies describing the Surgical patients represent a uniquely different cohort. elevated rates of VTE in medical patients who are Unlike medical patients, the primary reason for hospital hospitalised with COVID-19 on the ward or in the ICU, and admission for surgical patients is rarely due to COVID-19, results are pending for a number of ongoing randomised and other co-existing primary pathology requiring surgical controlled trials investigating VTE prophylaxis and intervention is also present. Surgical patients undergo an therapeutic protocols. To date, some studies describe operative procedure which artificially produces a wound increased bleeding risk with therapeutic (high) dosing of that increases the risk of intra-operative and postoperative pharmacological VTE prophylaxis [10], and interim analyses bleeding and sets in motion a cascade of inflammatory of several randomised controlled trials report unfavourable responses known to alter haemodynamics and coagulation. outcomes with therapeutic pharmacological prophylaxis in Paired with this, surgical patients often experience a period patients with severe COVID-19 (i.e. admitted to ICU). of reduced mobility immediately before, during and after © 2021 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists. 9 Anaesthesia 2021 COVIDSurg Collaborative and GlobalSurg Collaborative | SARS-CoV-2 infection and venous thromboembolism after surgery Table 4 Adjusted regression model for predictors for 30-day mortality. Values are fraction (proportion) or OR (95%CI) Mortality OR (95%CI) p value VTE status No VTE 2047/127,267 (1.6%) VTE 594/742 (20.0%) 5.42 (4.36–6.75) <0.001 SARS-CoV-2 status No SARS-CoV-2 1845/123,591 (1.5%) Peri-operative SARS-CoV-2 256/2317 (11.1%) 2.38 (2.00–2.82) <0.001 Recent SARS-CoV-2 70/953 (7.4%) 2.78 (2.09–3.71) <0.001 Previous SARS-CoV-2 24/1148 (2.1%) 1.13 (0.72–1.76) 0.597 Pneumonia No 1666/125,337 (1.3%) Yes 529/2672 (19.8%) 5.28 (4.65–6.00) <0.001 Age; y 18–49 429/57,557 (0.8%) 50–69 757/43,130 (1.8%) 1.62 (1.41–1.86) <0.001 ≥70 1009/27,320 (3.7%) 2.67 (2.31–3.10) <0.001 Sex Female 956/68,825 (1.4%) Male 1239/59,180 (2.1%) 1.06 (0.96–1.16) 0.269 ASA physical status 1–2 543/94,020 (0.6%) 3–5 1651/33,946 (4.9%) 4.32 (3.84–4.86) <0.001 Smoking No 1796/105,399 (1.7%) Yes 387/20,045 (1.9%) 1.16 (1.02–1.32) 0.021 Respiratory comorbidities No 1843/115,688 (1.6%) Yes 349/12,223 (2.9%) 0.95 (0.83–1.08) 0.410 Congestive heart failure No 1859/122,962 (1.5%) Yes 336/5019 (6.7%) 1.54 (1.34–1.78) < 0.001 Cerebral vascular disease No 1940/123,465 (1.6%) Yes 255/4516 (5.7%) 1.37 (1.18–1.60) < 0.001 Chronic kidney disease No 1884/124,644 (1.5%) Yes 311/3337 (9.3%) 2.32 (2.00–2.69) <0.001 Ischaemic heart disease No 1677/116,778 (1.4%) Yes 518/11,203 (4.6%) 1.01 (0.90–1.14) 0.842 Indication Benign 1174/78,720 (1.5%) Malignancy 569/24,112 (2.4%) 1.90 (1.68–2.14) <0.001 Trauma 413/15,236 (2.7%) 0.91 (0.80–1.04) 0.160 Obstetric 39/9938 (0.4%) 0.39 (0.27–0.55) <0.001 (continued) 10 © 2021 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists. COVIDSurg Collaborative and GlobalSurg Collaborative | SARS-CoV-2 infection and venous thromboembolism after surgery Anaesthesia 2021 Table 4 (continued) Mortality OR (95%CI) p value Grade of surgery Minor 388/48,596 (0.8%) Major 1807/79,388 (2.3%) 1.80 (1.59–2.03) <0.001 Urgency of surgery Elective 666/89,540 (0.7%) Emergency 1535/38,462 (4.0%) 5.62 (5.03–6.27) <0.001 Anaesthetic Local/regional 306/35,721 (0.9%) General 1888/92,235 (2.1%) 1.90 (1.65–2.18) <0.001 Country income High 1196/85,055 (1.4%) Upper middle 463/21,569 (2.2%) 2.43 (2.15–2.75) <0.001 Lower middle/low 536/21,385 (2.5%) 4.73 (4.17–5.37) <0.001 VTE, venous thromboembolism. Peri-operative SARS-CoV-2, 7 days before to 30 days after surgery; recent SARS-CoV-2, 1–6 weeks before surgery; previous SARS-CoV- 2, ≥ 7 weeks before surgery. their operation, even for the young and normally fit and clinical relevance of asymptomatic, distal DVT is uncertain healthy. Furthermore, elective surgical patients are a group and could lead to overdiagnosis and skewed results [1]. that can have a planned hospital admission, often following Venous thromboembolism diagnoses made in this study a period of self-isolation with reduced mobility, and many of were likely due to symptomatic presentation or a high index these patients will have peri-operative mechanical of clinical suspicion leading to radiological confirmation, ventilation. These differences in patient physiology and and we believe that the incidence of VTE in this study is exposure signify a need to define VTE risk specifically in representative of the true, clinically relevant figure. Third, surgical patients, not only to provide a baseline the rate of SARS-CoV-2 infection in October of 2020 and the understanding of peri-operative risk in the setting of overall incidence of VTE in surgical patients were both COVID-19, but also to work towards constructing future VTE relatively low. Despite the large number of patients in this regimens specifically suited to surgical patients with active study, some sub-group analyses have resulted in small or prior SARS-CoV-2 infection. patient samples, and these should be interpreted with This study has several limitations. First, information on caution. Finally, there exists the possibility that some postoperative VTE prophylaxis regimens (mechanical and patients who had SARS-CoV-2 infection never attained a pharmacological) and pre-existing anticoagulation for formal diagnosis and were therefore classified as no SARS- specific patient comorbidities associated with prophylaxis CoV-2. This most likely occurred in patients with (e.g. atrial fibrillation) were not collected as part of this asymptomatic infection. This study reported a high study. During the period of study (October 2020), patients proportion of patients with asymptomatic infection which with known SARS-CoV-2 infection might have already provides some reassurance that these cases were empirically received enhanced VTE prophylaxis based on appropriately counted. While asymptomatic patients could earlier reports associating COVID-19 and an increased risk have been misclassified as no SARS-CoV-2, this of VTE. The present study data report outcomes from VTE misclassification would have resulted in an underestimation care and prophylaxis which were deemed acceptable and of the overall difference in VTE between groups, and our appropriate for each individual patient in participating estimate could be considered conservative. departments from each country at the time of the study. Any Despite this study’s limitations, recent and peri- additional risk could be interpreted as risk above prevailing operative SARS-CoV-2 infection may be an independent VTE protocols and practice. Second, this study did not risk-factor for postoperative VTE, and increased awareness include patients who had an asymptomatic VTE diagnosed and surveillance should be considered. At a minimum, we as a result of screening. Though there are reports of VTE suggest close adherence to routine standard VTE screening being carried out in high-risk patient groups, the prophylaxis for surgical patients, including the use of © 2021 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists. 11 Anaesthesia 2021 COVIDSurg Collaborative and GlobalSurg Collaborative | SARS-CoV-2 infection and venous thromboembolism after surgery pharmacological agents when bleeding risk is minimal, and thromboembolism in hospitalized patients with COVID-19. Journal of Thrombosis and Haemostasis 2020; 18: 1859–65. increased vigilance with a heightened index of suspicion 8. National Institute for Health and Care Excellence. COVID-19 and a lower threshold for definitive diagnostic testing in rapid guideline: managing COVID-19. [NG191]. 23 March patients presenting with signs of VTE. Routine postoperative 2021, last updated 08 April 2021. https://www.nice.org.uk/ guidance/ng191 (accessed 24/05/2021). care of surgical patients should include interventions to 9. Conti CB, Henchi S, Coppeta GP, Testa S, Grassia R. Bleeding in reduce VTE risk in general, and further research is needed to COVID-19 severe pneumonia: the other side of abnormal define the optimal protocols for VTE prophylaxis and coagulation pattern? European Journal of Internal Medicine 2020; 77: 147–9. treatment for surgical patients in the setting of SARS-CoV-2 10. Leentjens J, van Haaps TF, Wessels PF, Schutgens REG, infection. Middeldorp S. COVID-19-associated coagulopathy and antithrombotic agents-lessons after 1 year. Lancet Haematology 2021; 8: e524–33. Acknowledgements 11. Ev E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, This study was registered prospectively at clinicaltrials.gov Vandenbroucke JP. Strengthening the reporting of observational studies in epidemiology (STROBE) statement: (NCT04509986). Funding was provided by: National guidelines for reporting observational studies. British Medical Institute for Health Research (NIHR) Global Health Research Journal 2007; 335: 806–8. Unit; Association of Coloproctology of Great Britain and 12. Collaborative C, Collaborative G. Timing of surgery following SARS-CoV-2 infection: an international prospective cohort Ireland; Bowel and Cancer Research; Bowel Disease study. Anaesthesia 2021; 76: 748–58. Research Foundation; Association of Upper Gastrointestinal 13. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Surgeons; British Association of Surgical Oncology; British Research electronic data capture (REDCap)—a metadata- driven methodology and workflow process for providing Gynaecological Cancer Society; European Society of translational research informatics support. Journal of Coloproctology; Medtronic; NIHR Academy; Sarcoma UK; Biomedical Informatics 2009; 42: 377–81. 14. World Bank. World Bank Country and Lending Groups. 2021. The Urology Foundation; Vascular Society for Great Britain https://datahelpdesk.worldbank.org/knowledgebase/articles/ and Ireland; and Yorkshire Cancer Research. The views 906519-world-bank-country-and-lending-groups (accessed expressed are those of the authors and not necessarily those 24/03/2021). 15. ATTACC Investigators. ACTIV-4a & REMAP-CAP multiplatform of the funding partners. No other competing interests RCT - Results of interim analysis. 2021. https://www.attacc.org/ declared. presentations (accessed 24/03/2021). References Supporting Information 1. Longchamp G, Manzocchi-Besson S, Longchamp A, Righini M, Additional supporting information may be found online via Robert-Ebadi H, Blondon M. Proximal deep vein thrombosis and pulmonary embolism in COVID-19 patients: a systematic the journal website. review and meta-analysis. Thrombosis Journal 2021; 19: 15. Appendix S1. COVIDSurg Collaborative authors (all 2. Nopp S, Moik F, Jilma B, Pabinger I, Ay C. Risk of venous PubMed indexed co-authors). thromboembolism in patients with COVID-19: a systematic review and meta-analysis. Research and Practice in Thrombosis Appendix S2. Definitions of terms used in this study. and Haemostasis 2020; 4: 1178–91. Tables S1. List of excluded procedures. 3. Al-Ani F, Chehade S, Lazo-Langner A. Thrombosis risk Tables S2. Ranked VTE rates alongside PE and DVT associated with COVID-19 infection. A scoping review. Thrombosis Research 2020; 192: 152–60. rates by specialty in all patients of any SARS-CoV-2 status 4. Porfidia A, Valeriani E, Pola R, Porreca E, Rutjes AW, Di Nisio M. Tables S3. Adjusted regression model for factors Venous thromboembolism in patients with COVID-19: systematic review and meta-analysis. Thrombosis Research associated with venous thromboembolism (shown in 2020; 196: 67–74. Figure 3). 5. Potere N, Valeriani E, Candeloro M, et al. Acute complications Tables S4. Adjusted sub-group analysis for VTE in and mortality in hospitalized patients with coronavirus disease 2019: a systematic review and meta-analysis. Critical Care 2020; elective patients only. 24: 389. Tables S5. Adjusted sub-group analysis for VTE in 6. Malas MB, Naazie IN, Elsayed N, Mathlouthi A, Marmor R, Clary emergency patients only. B. Thromboembolism risk of COVID-19 is high and associated with a higher risk of mortality: a systematic review and meta- Tables S6. Adjusted sub-group analysis for VTE in analysis. EClinicalMedicine 2020; 29: 100639. major surgery patients only. 7. Spyropoulos AC, Levy JH, Ageno W, et al. Scientific and Tables S7. Adjusted sub-group analysis for VTE in Standardization Committee communication: clinical guidance on the diagnosis, prevention, and treatment of venous minor surgery patients only. 12 © 2021 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists.