Disclosures and mitigating statements:
Charles Au, B.Sc.(Pharm.), ACPR, PharmD. Disclosures: Received funding from Vancouver Coastal Health Research Institute – research grant for new researchers for a retrospective study on opioid use disorder. Mitigating potential bias: Treatments or recommendations in this article are unrelated to products/services/treatments involved in disclosure statements.
Tristen Gilchrist, MD, MSc (HPE), FRCPC. Disclosures: Received funding from Royal College of Physicians and Surgeons of Canada – Medical Education Research Grant. Mitigating potential bias: Only published trial data is presented. Recommendations are consistent with published guidelines, as indicated in the article. Recommendations in this article are unrelated to funded research involved in disclosure statements.
Agnes Y Y Lee, MD, MSc, FRCPC: Disclosures: Received funding for research from Bristol Myers Squibb. Member of advisory boards or speakers’ bureaus: Bayer, LEO Pharma, Pfizer, and Servier. Mitigating potential bias: Only published trial data are included. Recommendations are consistent with published guidelines (ACCP, ASH). Recommendations are consistent with current practice patterns. All potential conflicts are disclosed.
What we did before
Hospitalized patients are at increased risk of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE). (1) Most medical patients have at least one risk factor for VTE and 50-75% of hospital-acquired VTE events occur in medical patients. (1)
In 2011, Accreditation Canada instituted a Required Organizational Practice (ROP) for VTE prophylaxis, requiring that hospitals identify and provide appropriate thromboprophylaxis to adult patients at risk of VTE. (2,3) This led to widespread implementation of VTE prophylaxis risk assessment and thromboprophylaxis orders on hospital admission pre-printed order sets, and as a result, thromboprophylaxis use in medical patients in Canada increased substantially from 17% in 2007 to 80-90% in recent years. (4-6) Currently, pharmacologic thromboprophylaxis is routinely ordered for hospitalized medical patients unless they are fully ambulatory with an anticipated short stay or are bleeding or at high risk of bleeding.
Thromboprophylaxis with unfractionated heparin or low-molecular-weight heparin reduces the risk of VTE in hospitalized medical patients; however, the evidence has significant limitations. These studies screened all enrolled patients for asymptomatic DVTs (present in 10-20% of medical inpatients) rather than only imaging patients with clinically-suspected VTE. (1,7-9) In a Cochrane systematic review of 16 trials (with a total of 34,369 participants) in acutely ill medical patients, thromboprophylaxis reduced the risk of asymptomatic DVT (OR 0.41, 95% CI 0.25-0.67) compared to placebo or no treatment, but did not reduce all-cause mortality or pulmonary embolism (PE) and increased the risk of major bleeding (OR 1.65, 95% CI 1.01-2.71). (10) In addition, the literature is outdated and does not reflect the shorter lengths of stay and increased attention to early mobilization in current practice. Based on more contemporary studies, <2% of medical inpatients develop a symptomatic VTE within 3 months of admission. (11)
What changed our practice
Risk assessment models (RAMs) have been developed to identify those at higher VTE risk who may warrant thromboprophylaxis. Use of RAMs to guide prescribing of thromboprophylaxis is suggested by the most recent American College of Chest Physicians and the American Society of Hematology guidelines. (1,7) The two best-studied RAMs for medical inpatients are the Padua score and the IMPROVE VTE score, with the IMPROVE VTE score being easier to use (only 7 items compared to 11 items in the Padua score) and showing more consistent performance in multiple external validation studies. (12-17)
The IMPROVE VTE score was derived from an international cohort of 15,156 adults hospitalized for at least 3 days with an acute medical illness (excluding patients on anticoagulation or those admitted with a VTE). (18,19) Subjects were hospitalized with common medical conditions including cardiac disease (39%), infection (32%), respiratory failure (19%) and cancer (12%), and 44% received pharmacological thromboprophylaxis. Within 92 days of admission, 1% of subjects had experienced a VTE event (defined as a VTE confirmed by imaging and for which the patient received treatment). Subjects with an IMPROVE VTE score of 0 or 1 (representing 69% of the study cohort) had a VTE rate of 0.5%, whereas subjects with an IMPROVE VTE score of 2 or more (31% of the study cohort) had a VTE rate of 2.4%. The IMPROVE VTE score showed fair discrimination with a c-statistic of 0.69 (a c-statistic of 0.5 indicates a model is not better than chance, whereas a c-statistic of 1 indicates a perfect model).
There are some important limitations with utilizing the IMPROVE VTE RAM to guide thromboprophylaxis prescribing. Three of the score components (lower limb paralysis, immobilization for at least 7 days, and ICU/CCU stay) were derived from characteristics of the hospital stay, and so were not available upon admission. Immobilization was defined as being confined to a bed or chair; however, the characteristics of subjects’ immobility were not reported and it is unclear how the threshold of 7 days was chosen. Patients who were pregnant, were critically ill or admitted with stroke were under-represented or excluded in the IMPROVE VTE studies.
What we do now
We calculate an IMPROVE VTE score in patients hospitalized for an acute medical illness by adding up points for any confirmed or suspected risk factors present upon admission (see Table 1). Alternatively, the probability of symptomatic VTE can be estimated using the IMPROVE model calculator located at https://www.outcomes-umassmed.org/IMPROVE/risk_score/index.html. (20)
Table 1. IMPROVE VTE score. (18)
|VTE risk factor||Points|
|Lower limb paralysis||2|
|Immobilization for at least 7 days**||1|
|Age greater than 60 years||1|
* Familial or acquired disorders of the hemostatic system that result in an increased risk of thrombosis. Examples include: antithrombin deficiency, resistance to activated protein C, protein C and protein S deficiencies, prothrombin gene mutation, Factor V Leiden, antiphospholipid syndrome.
** Includes days spent immobile immediately prior to admission as well as during hospital admission
We consider thromboprophylaxis in patients with an IMPROVE VTE score of 2 or greater. Medical patients with an IMPROVE VTE score of 0 or 1 have an estimated baseline 3-month VTE risk of <1% and are unlikely to benefit from thromboprophylaxis. (1,7,21) We reassess the indication for VTE prophylaxis regularly throughout a patient’s hospitalization, such as for a diagnosis of active cancer or for changes in mobility. However, as few as 4% of patients initially considered low risk for VTE become high risk during their admission. (22)
Of note, hospitalized patients with suspected or confirmed active COVID-19 infection have a high risk of thrombosis regardless of their IMPROVE VTE score and should receive thromboprophylaxis unless contraindicated. (23)
- Pharmacologic thromboprophylaxis is routinely ordered for patients who are hospitalized for an acute medical illness; however, many medical patients are at low risk for hospital-acquired VTE.
- The IMPROVE VTE score is an externally validated tool that can be used to identify low-risk medical patients who do not warrant VTE prophylaxis.
- Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(suppl 2):e195S-e226S. DOI: 10.1378/chest.11-2296. (View)
- Accreditation Canada. Required Organizational Practices Handbook 2020. 2020. (Request with CPSBC)
- Kotaska A. Venous thromboembolism prophylaxis may cause more harm than benefit: An evidence-based analysis of Canadian and international guidelines. Thromb J. 2018;16:25. DOI: 10.1186/s12959-018-0180-6. (View)
- Kahn SR, Panju A, Geerts W, et al. Multicenter evaluation of the use of venous thromboembolism prophylaxis in acutely ill medical patients in Canada. Thromb Res. 2007;119(2):145‐155. DOI: 10.1016/j.thromres.2006.01.011. (View with CPSBC or view with UBC)
- Mejilla A, Guirguis M, Koshman S, Bungard TJ. Venous thromboembolism prophylaxis on general internal medicine units: Are patients well served by current practice? Can J Hosp Pharm. 2017;70(3):200-206. DOI: 10.4212/cjhp.v70i3.1659. (View)
- Canadian Patient Safety Institute. Accreditation Canada recognizes increasing compliance with VTE prophylaxis. June 2, 2016. https://www.patientsafetyinstitute.ca/en/NewsAlerts/News/Pages/Accreditation-Canada-recognizes-increasing-compliance-with-VTE-prophylaxis.aspx. (View)
- Schunemann HJ, Cushman M, Burnet AE, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients. Blood Adv. 2018;2(22):3198-3225. DOI: 10.1182/bloodadvances.2018022954. (View)
- Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(suppl 6):381S-453S. DOI: 10.1378/chest.08-0656. (Request with CPSBC or view with UBC)
- Therapeutics Initiative. Routine VTE prophylaxis: Is there a net health benefit? July 15, 2019. https://www.ti.ubc.ca/2019/07/15/120-routine-vte-prophylaxis-is-there-a-net-health-benefit/. (View)
- Alikhan R, Bedenis R, Cohen AT. Heparin for the prevention of venous thromboembolism in acutely ill medical patients (excluding stroke and myocardial infarction). Cochrane Database Syst Rev. 2014;(5):CD003747. DOI: 10.1002/14651858.CD003747.pub4. (View)
- Edelsberg J, Hagiwara M, Taneja C, Oster G. Risk of venous thromboembolism among hospitalized medically ill patients. Am J Health-Syst Pharm. 2006;63(20 suppl 6):S16-22. DOI: 10.2146/ajhp060389. (View with CPSBC or view with UBC)
- Barbar S, Noventa F, Rossetto V, et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: The Padua Prediction Score. J Thromb Haemost. 2010;8(11):2450-2457. DOI: 10.1111/j.1538-7836.2010.04044.x. (View)
- Vardi M, Ghanem-Zoubi NO, Zidan R, Yurin V, Bitterman H. Venous thromboembolism and the utility of the Padua Prediction Score in patients with sepsis admitted to internal medicine departments. J Thromb Haemost. 2013;11(3):467-473. DOI: 10.1111/jth.12108. (View)
- Germini F, Agnelli G, Fedele M, et al. Padua prediction score or clinical judgment for decision making on antithrombotic prophylaxis: A quasi-randomized controlled trial. J Thromb Thrombolysis. 2016;42(3):336-339. DOI: 10.1007/s11239-016-1358-z. (Request with CPSBC or view with UBC)
- Rosenberg D, Eichorn A, Alarcon M, McCullagh L, McGinn T, Spyropoulos AC. External validation of the risk assessment model of the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) for medical patients in a tertiary health system. J Am Heart Assoc. 2014;3:e001152. DOI: 10.1161/JAHA.114.001152. (View)
- Mahan CE, Liu Y, Turpie AG, et al. External validation of a risk assessment model for venous thromboembolism in the hospitalised acutely-ill medical patient (VTE-VALOURR). Thromb Haemost. 2014;112(4):692-699. DOI: 10.1160/TH14-03-0239. (Request with CPSBC or view with UBC)
- Cobben MRR, Nemeth B, Lijfering WM, Cannegieter SC. Validation of risk assessment models for venous thrombosis in hospitalized medical patients. Res Pract Thromb Haemost. 2019;3:217-225. DOI: 10.1002/rth2.12181. (View)
- Spyropoulos AC, Anderson Jr FA, FitzGerald G, et al. Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest. 2011;140(3):706-714. DOI: 10.1378/chest.10-1944. (View with CPSBC or view with UBC)
- Tapson VF, Decousus H, Pini M, et al. Venous thromboembolism prophylaxis in acutely ill hospitalized medical patients: Findings from the International Medical Prevention Registry on Venous Thromboembolism. Chest. 2007;132(3):936-945. DOI: 10.1378/chest.06-2993. (Request with CPSBC or view with UBC)
- International Medical Prevention Registry on Venous Thromboembolism (IMPROVE). IMPROVE risk score. https://www.outcomes-umassmed.org/IMPROVE/risk_score/index.html. (View)
- Le P, Martinez KA, Pappas MA, Rothberg MB. A decision model to estimate a risk threshold for venous thromboembolism prophylaxis in hospitalized medical patients. J Thromb Haemost. 2017;15(6):1132-1141. DOI: 10.1111/jth.13687. (View)
- Tung EC, Yu S, Shah K, et al. Reassessment of venous thromboembolism and bleeding risk in medical patients receiving VTE prophylaxis. J Eval Clin Pract. 2020;26(1):18-25. DOI: 10.1111/jep.13213. (View with CPSBC or view with UBC)
- Cuker A, Tseng EK, Nieuwlaat R, et al. American Society of Hematology 2021 guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19. Blood Adv. 2021;5 (3): 872-888. DOI: 10.1182/bloodadvances.2020003763. (View)