The CLUE postsurgery VTE risk instrument for abdominal and pelvic surgery: validation of patient risk factor component Open Access

Each year, surgeons perform >300 million procedures worldwide.¹ Despite advances in surgical and perioperative care,² venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, remains an important cause of postoperative morbidity and mortality.^3-5 

Surgeons have widely adopted the use of anticoagulants as a preventative strategy against VTE.^3-5 Because the risks of postoperative VTE and bleeding vary according to patient- and procedure-specific factors,^6-10 the thromboprophylaxis decisions require balancing the reduction in VTE risk against the increased risk of bleeding.¹¹ Historically, guidelines in general abdominal surgery, gynecology, and urology have recommended pharmacologic prophylaxis perioperatively for patients at higher VTE risk. These recommendations did not, however, provide clear criteria for determining the risk level of specific procedures or patients,¹² an omission that has contributed to substantial practice variation.^13-15 In urology, this gap was in part addressed in 2017 when the European Association of Urology (EAU) introduced the first procedure-specific thromboprophylaxis guidelines in abdominal and pelvic surgeries.⁴ 

Risk of VTE and bleeding across procedures represents a key issue in deciding on prophylaxis, but individual patient risk factors is also important. Investigators have developed several VTE risk assessment models for surgical patients, including Caprini, Rogers, Kucher, and CHAT scores, as well as Pannucci VTE risk model and American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) Universal Surgical Risk Calculator.^16-22 However, their predictive performance remains modest, with no single risk assessment model demonstrating clear superiority. Furthermore, many are excessively complex or have limited applicability.^23,24 

The EAU thromboprophylaxis guidelines were informed by systematic reviews that provided baseline VTE risk estimates for >30 urologic procedures, incorporating both procedure- and patient-specific risk factors.^6,7 Recently, extensive systematic reviews provided similar procedure-specific VTE and bleeding estimates for general abdominal, colorectal, upper gastrointestinal, hepatopancreatobiliary, and both cancer and noncancer gynecologic surgeries.^8-10 Although these guidelines and systematic reviews represent an advance in providing procedure-specific, rigorous evidence, the patient stratification instrument used has not yet been validated. To address this, we used data from a large, prospective study (VISION) to validate the patient risk factor component of what we call the CLUE postsurgery VTE risk instrument.

We followed the STROBE (Strengthening the Reporting of Observational Studies on Epidemiology) reporting guideline for cohort studies.²⁵ 

The CLUE postsurgery VTE risk instrument was developed through systematic reviews and meta-analyses that informed the EAU thromboprophylaxis in urologic surgery guideline.² These reviews stratified the risk of VTE not only by the type of procedure but also by patient-specific VTE risk factors.^6,7 Although initially applied in the context of a urologic surgery guideline, this straightforward instrument was from its initialization designed for general abdominal, urologic, and gynecologic surgeries and constructed based on the most pertinent and robust evidence from a literature review focusing on VTE risk factors.²⁶ 

The initial version of the instrument²⁶ included the following patient-specific VTE risk factors: (1) age ≥75 years; (2) body mass index (BMI) ≥35 kg/m²; and (3) a history of VTE in a first-degree relative (parents, full siblings, or children). We selected these thresholds based on evidence indicating that each factor approximately doubles the risk of VTE.²⁶ Prior VTE or any combination of these risk factors increased the risk fourfold. Given that information about first-degree relatives often remains unknown, we simplified the instrument. The revised CLUE postsurgery VTE risk instrument²⁷ includes the following: (1) age ≥75 years; (2) BMI ≥35 kg/m² (both factors approximately doubling the risk); and (3) prior VTE, the most critical patient risk factor, with a risk ratio (RR) of ∼4.

Using these criteria, the instrument categorizes patients (by relative risk) into low- (reference), medium- (estimated RR of 2), and high-risk (estimated RR of 4) categories for VTE. The designations high and medium refer not to the absolute risk but rather increases in risk relative to low-risk patients. Thus, for instance, patients undergoing a surgical procedure with a very low risk of VTE could be in a high individual risk category but have a low absolute risk of VTE.

For the evaluation of the CLUE instrument, we used data from the VISION study, a prospective cohort study of 40 004 patients aged >45 years who underwent inpatient noncardiac surgery between 2007 and 2013 at 28 centers in 14 countries (ClinicalTrials.gov identifier: NCT00512109).²⁸ The ethics review board at each participating center approved the VISION study protocol. The details and methods of the VISION study have been described previously.^28,29 

All eligible patients, aged ≥45 years, underwent noncardiac surgery requiring overnight hospital admission after surgery. Study personnel identified potential participants through daily screening of patient lists in preoperative assessment clinics, surgical lists from the same and previous days, lists on surgical wards and in intensive care units, and in preoperative holding areas. Enrolled patients answered a series of questions about their past medical and social history. Research personnel reviewed medical charts for further background history, noted outcome events throughout the hospital stay, and conducted a follow-up telephone interview with the patient or their next-of-kin 30 days after surgery. Research staff obtained further documentation if the interview indicated the occurrence of an outcome event. Investigators reviewed and approved data at each site. Research personnel submitted case report forms and supporting documentation directly to the coordinating center. Data monitoring involved central data consistency checks, statistical monitoring, and on-site monitoring for all centers.

Among patients undergoing major general abdominal, urologic, or gynecologic surgeries, we assessed 30-day postoperative VTE across the 3 CLUE risk categories: low (no risk factors), medium (either age ≥75 years or BMI ≥35 kg/m²), and high risk (prior VTE or both age ≥75 years and BMI ≥35 kg/m², with or without prior VTE). VTE was defined as either a pulmonary embolism, confirmed by computed tomography, angiography, or ventilation/perfusion lung scan, or a deep vein thrombosis in the leg or arm, confirmed by venography, compression ultrasonography, or computed tomography.²⁸ To estimate RRs, we used modified Poisson regression¹⁵ across VTE risk groups overall and stratified by the use of antithrombotic agents in the first 3 days after surgery. Wald-type tests provided 2-sided P values; we considered P value <.05 as statistically significant. Because our aim was prognostic, evaluating the performance of the CLUE postsurgery VTE risk instrument rather than estimating causal effects, we did not adjust for additional variables outside the tool.

The ethics review board at each participating center approved the VISION study protocol.

Our analysis included 11 636 major general abdominal, urologic, and gynecologic surgery patients. Figure 1 presents the flow chart. The median age of the patients was 62 years (interquartile range, 54-71), the median BMI was 26.3 kg/m² (interquartile range, 23.2-30.0), and 5797 patients (49.8%) were women. Using patient-specific VTE risk factors (reflecting relative risk rather than absolute risk, as previously described), we classified 8329 patients (72%) as low VTE risk, 2853 (25%) as medium risk, and 454 (4%) as high risk. Of the included patients, 1198 (10.3%) underwent urgent or emergency surgery. Table 1 describes more details of the study population.

Of the 11 636 patients, 97 (0.8%) experienced VTE within 30 days after surgery. Compared to the low-risk (reference) group, RRs across categories of the risk instrument were 1.56 (95% confidence interval [CI], 1.01-2.43; P = .047) for medium-risk and 3.60 (95% CI 1.90-6.83; P < .001) for high-risk patients (Figure 2; Table 2).

Relative risks were numerically higher for patients who did not receive antithrombotic agents in the first 3 days after surgery (medium risk [RR, 1.91; 95% CI, 0.90-4.04] and high risk [RR, 5.41; 95% CI, 1.29-22.6]) than those who did (medium risk [RR, 1.32; 95% CI, 0.77-2.29] and high risk [RR, 2.86; 95% CI, 1.33-5.90]; Table 3). These differences were not statistically significant, and the interaction test (P = .60) suggests that chance likely explains the variation between groups.

This secondary analysis of a large prospective cohort study validated the relative differences in VTE risk between the patient risk factor categories of the CLUE postsurgery VTE risk instrument. When combined with known procedure-specific absolute risks,^7-11 this straightforward instrument, requiring only information about patient’s age, BMI, and VTE history, offers a practical and evidence-based method for estimating VTE risk in general abdominal, urologic, and gynecologic surgeries.

Strengths of the study include, first, the use of a large, diverse international sample of >11 000 surgical patients. Second, we followed a prespecified statistical analysis approach. Third, the CLUE postsurgery VTE risk instrument is simple, user-friendly, and complements procedure-specific VTE and bleeding risk estimates by further stratifying patients into distinct risk categories. To improve accessibility, we have developed an online tool that provides clinicians with tailored absolute risk estimates for VTE and bleeding in general abdominal, urologic, and gynecologic surgery. The tool is available at www.ClueVTE.org.

This study also has limitations. First, patients in the VISION study underwent surgery between October 2008 and December 2013. Since then, perioperative care has evolved, with increased use of minimally invasive techniques, improved anesthetic practices, enhanced intraoperative monitoring, and faster postoperative mobilization.² Because absolute VTE risks are likely sensitive to these changes, our study may overestimate current risk levels. However, we conjecture that even with a lower incidence of postoperative VTE, patient-related risk factors, which is the focus of this article, would remain largely unaffected. Second, a significant proportion of eligible patients (31.5%) in the VISION study were not enrolled, primarily due to patient nonconsent. Although the distribution of VTE risk factors may have differed among nonparticipants, potentially affecting the study results, it is more likely to affect absolute risk estimates rather than the relative differences observed in our study. Furthermore, the relative risk estimates observed here are consistent with those reported in earlier studies on which the CLUE instrument was based,²⁶ supporting their validity and generalizability. Finally, due to the relatively low incidence of VTE events, the precision of stratified analyses was limited.

Although the CLUE postsurgery VTE risk instrument provides useful estimates based on procedure type and key patient factors (BMI, age, and prior VTE), it is not a substitute for clinical judgment. In some cases, additional factors beyond the instrument’s scope influence thromboprophylaxis decisions, underscoring the need for individualized assessment. Nevertheless, this new straightforward instrument, which also provides, besides patient- and procedure-specific VTE risks, procedure-specific bleeding risks,^7-11 has the potential to rationalize VTE prevention practices worldwide, ultimately enhancing patient care across surgical specialties.

In conclusion, among patients undergoing general abdominal, urologic, or gynecologic surgeries in a large international cohort study, the relative differences in VTE risk across categories of the CLUE postsurgery VTE risk instrument were aligned with those predicted by literature-derived weights. By combining 3 patient-level factors with procedure-specific information, the instrument reliably stratifies relative VTE risk and complements absolute risk estimates. An interactive online version is now available to support evidence-based thromboprophylaxis decisions.

K.A.O.T. (Finland) received funding from Research Council of Finland (276046 and 340957), Competitive Research Funding of the Helsinki University Hospital (TYH2022330 and TYH2023236), Finnish Cultural Foundation, Finnish Medical Foundation, Jane and Aatos Erkko Foundation, Sigrid Juselius Foundation, and Vyborg Tuberculosis Foundation. D.S. (Canada) was supported by Government of Canada/Canada Research Chairs Program (Tier 2 Canada Research Chair in Anticoagulant Management of Cardiovascular Disease). P.J.D. (Canada) was supported by Roche Diagnostics, which provided the troponin T assays as well as financial support for the VISION study. Funding for this study came from >70 grants for VISION and its substudies: in Canada, Canadian Institutes of Health Research (7 grants); Heart and Stroke Foundation of Ontario (2 grants); Academic Health Science Centres Alternative Funding Plan Innovation Fund Ontario; Population Health Research Institute; CLARITY Research Group; McMaster University Department of Surgery Surgical Associates; Hamilton Health Science New Investigator Fund; Hamilton Health Sciences; Ontario Ministry of Resource and Innovation; Stryker Canada; McMaster University, Department of Anesthesiology (2 grants); St. Joseph’s Healthcare, Department of Medicine (2 grants); Father Sean O’Sullivan Research Centre (2 grants); McMaster University Department of Medicine (2 grants); Roche Diagnostics Global Office (5 grants); Hamilton Health Sciences Summer Studentships (6 grants); McMaster University Department of Clinical Epidemiology and Biostatistics; McMaster University, Division of Cardiology; Canadian Network and Centre for Trials Internationally; Winnipeg Health Sciences Foundation; University of Manitoba Department of Surgery (2 grants); Diagnostic Services of Manitoba Research; Manitoba Medical Services Foundation; Manitoba Health Research Council; University of Manitoba Faculty of Dentistry Operational Fund; University of Manitoba Department of Anesthesia; and University Medical Group, Department of Surgery, University of Manitoba, Start-up Fund; in Australia, National Health and Medical Research Council Program; in Brazil (to P.J.D.), Projeto Hospitais de Excelência a Serviço do SUS (PROADI-SUS) grant from the Brazilian Ministry of Health in partnership with Hcor (Cardiac Hospital Sao Paulo–SP); and National Council for Scientific and Technological Development (CNPq) grant from the Brazilian Ministry of Science and Technology; in China (to P.J.D.), Public Policy Research Fund (grant CUHK-4002-PPR-3), Research Grant Council, Hong Kong SAR; General Research Fund (grant 461412), and Research Grant Council, Hong Kong SAR; in Australia/New Zealand (to P.J.D.), Australian and New Zealand College of Anaesthetists (grant 13/008); in Colombia (to P.J.D.), School of Nursing, Universidad Industrial de Santander; Grupo de Cardiología Preventiva, Universidad Autónoma de Bucaramanga; Fundación Cardioinfantil–Instituto de Cardiología; and Alianza Diagnóstica SA; in France (to P.J.D.), Université Pierre et Marie Curie, Département d’anesthésie Réanimation, Pitié-Salpêtrière, Assistance Publique–Hôpitaux de Paris; in India (to P.J.D.), Division of Clinical Research and Training, St John’s Medical College and Research Institute; in Malaysia (to P.J.D.), University of Malaya (grant RG302-14AFR); and University of Malaya, Penyelidikan Jangka Pendek; in Poland (to P.J.D.), Polish Ministry of Science and Higher Education (grant NN402083939); in South Africa (to P.J.D.), University of KwaZulu-Natal. Devereaux (Spain): Instituto de Salud Carlos III; and Fundació La Marató de TV3; in the United States (to P.J.D.), American Heart Association; Covidien; and American Society of Nephrology Student Scholar Grant; and in the United Kingdom (to P.J.D.), from National Institute for Health Research. S.V.T. (Finland) received funding from Finnish Medical Foundation. F.K.B. (Canada) was supported by Hamilton Health Sciences (Early Career Research Award) and P.S.R. (Canada) by Academic Medical Organization of Southwestern Ontario.

The funders had no role in the study design, data collection, analysis, or interpretation, or in the manuscript preparation, review, or approval.

Contribution: P.S.R. had full access to all the data in the study and takes responsibility for the integrity of data and the accuracy of data analysis; K.A.O.T., P.J.D., G.H.G., and P.S.R. conceptualized and designed the study; K.A.O.T., D.S., P.J.D., S.V.T., F.K.B., S.O., J.P., B.S., L.I.L., and P.S.R. acquired data; K.A.O.T., P.J.D., S.V.T., L.I.L., G.H.G., and P.S.R. analyzed and interpreted data; K.A.O.T., G.H.G., and P.S.R. performed statistical analysis; K.A.O.T., S.V.T., and P.S.R. drafted the manuscript; K.A.O.T. and P.J.D. obtained funding; P.J.D. provided administrative, technical, and material support; K.A.O.T. and P.S.R. supervised the study; and all authors critically revised the manuscript for important intellectual content.

Conflict-of-interest disclosure: D.S. reported honoraria paid to her institution from AstraZeneca, Bristol Myers Squibb-Pfizer, Roche, and Servier, unrelated to the current work. P.J.D. reported receiving grants from Abbott Diagnostics, AOP Pharma, Renibus, Roche Diagnostics, and Siemens; monitoring services from CloudDX and Philips Healthcare; serving as a consultant for Abbott Diagnostics, AstraZeneca, Bayer, Roche Canada, and Trimedic; and serving as an advisory board member for Bayer and Quidel outside the submitted work. F.K.B. reported receiving investigator-initiated grants from Roche Diagnostics and Siemens, unrelated to the current work. K.A.O.T. was chair of the European Association of Urology Guideline on Thromboprophylaxis in Urological Surgery; a panel member of the American Society of Hematology Thromboprophylaxis guideline on prevention of venous thromboembolism (VTE) in surgical hospitalized patients; and urology subgroup chair of the European Society of Anesthesiology and Intensive Care Task Force for the European Guidelines on VTE. G.H.G. was a panel member of the European Association of Urology Guideline on Thromboprophylaxis in Urological Surgery. The remaining authors declare no competing financial interests.

A complete list of collaborator authors of CLUE Postsurgery VTE Risk Instrument Group appears in “Appendix.”

Correspondence: Kari A. O. Tikkinen, Department of Urology, University of Helsinki and Helsinki University Hospital, Biomedicum 2 B, P.O. Box 13, Tukholmankatu 8 B, 00290, Helsinki, Finland; email: kari.tikkinen@helsinki.fi.

Collaborator authors (CLUE PostSurgery VTE Risk Instrument Group): Riikka L. Aaltonen, Arnav Agarwal, Chika Agbassi, Kaisa Ahopelto, Bassel Ali, Karoliina M. Aro, Ines Beilmann-Lehtonen, Marco H. Blanker, Kostiantyn Bolsunovskyi, Rufus Cartwright, Jovita L. Cárdenas, Samantha Craigie, Rachel J. Couban, Jaana Elberkennou, Leyla Eryuzlu, Päivi J. Galambosi, Herney A. Garcia-Perdomo, Fang Zhou Ge, Johanna Geraci, Michael K. Gould, Huda A. Gomaa, Rachel Gutschon, Alex L. E. Halme, Jari Haukka, Maha Imam, Nofisat Ismaila, Matthew L. Izett-Kay, Ilkka E. J. Kalliala, Paul J. Karanicolas, Denise Kam, Nadina Khamani, Tuomas P. Kilpeläinen, Antti J. Kivelä, Kirsi M. Joronen, Hanna Lampela, Yung Lee, Anna L. Luomaranta, Anne K. Mattila, Giacomo Novara, Richard Naspro, Taina P. Nykänen, Sanna M. Oksjoki, Sanjay Pandanaboyana, Negar Pourjamal, Chathura B. B. Ratnayake, Aleksi R. Raudasoja, Ville J. Sallinen, Per Morten Sandset, Reed A. Siemieniuk, Tino Singh, Riikka M. Tähtinen, Borna Tadayon Najafabadi, Philippe D. Violette, Robin W. M. Vernooij, Yuting Wang, Yingqi Xiao, Liang Yao, and Daniel Yoo.