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Semin Respir Crit Care Med 2021; 42(02): 308-315
DOI: 10.1055/s-0041-1723018
Review Article

Prevention of Venous Thromboembolism in Acutely Ill Medical Patients: A New Era

Kira MacDougall
1   Department of Internal Medicine, Northwell Health at Staten Island University Hospital, Staten Island, New York
,
Alex C. Spyropoulos
2   Center for Health Innovations and Outcomes Research, The Feinstein Institutes for Medical Research and Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York
3   Department of Medicine, Anticoagulation and Clinical Thrombosis Services, Northwell Health at Lenox Hill Hospital, New York, New York
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Abstract

Venous thromboembolism (VTE) is the leading preventable cause of death in hospitalized patients and data consistently show that acutely ill medical patients remain at increased risk for VTE-related morbidity and mortality in the post-hospital discharge period. Prescribing extended thromboprophylaxis for up to 45 days following an acute hospitalization in key patient subgroups that include more than one-quarter of hospitalized medically-ill patients represents a paradigm shift in the way hospital-based physicians think about VTE prevention. Advances in the field of primary thromboprophylaxis in acutely-ill medical patients using validated VTE and bleeding risk assessment models have established key patient subgroups at high risk of VTE and low risk of bleeding that may benefit from both in-hospital and extended thromboprophylaxis. The direct oral anticoagulants betrixaban and rivaroxaban are now U.S. Food and Drug Administration-approved for in-hospital and extended thromboprophylaxis in medically ill patients and provide net clinical benefit in these key subgroups. Coronavirus disease-2019 may predispose patients to VTE due to excessive inflammation, platelet activation, endothelial dysfunction, and hemostasis. The optimum preventive strategy for these patients requires further investigation. This article aims to review the latest concepts in predicting and preventing VTE and discuss the new era of extended thromboprophylaxis in hospitalized medically ill patients.

Keywords

venous thromboembolism - medically ill patients - critical care - direct oral anticoagulants - extended thromboprophylaxis - deep vein thrombosis - pulmonary embolism


Publication History

Article published online:
06 February 2021

© 2021. Thieme. All rights reserved.

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  • References

  • 1 Goldhaber SZ, Bounameaux H. Pulmonary embolism and deep vein thrombosis. Lancet 2012; 379 (9828): 1835-1846
    CrossrefPubMedGoogle Scholar
  • 2 Anderson Jr FA, Zayaruzny M, Heit JA, Fidan D, Cohen AT. Estimated annual numbers of US acute-care hospital patients at risk for venous thromboembolism. Am J Hematol 2007; 82 (09) 777-782
    CrossrefPubMedGoogle Scholar
  • 3 Miao B, Chalupadi B, Clark B. et al. Proportion of US hospitalized medically ill patients who may qualify for extended thromboprophylaxis. Clin Appl Thromb Hemost 2019; 25: 1076029619850897 DOI: 10.1177/1076029619850897.
    CrossrefPubMedGoogle Scholar
  • 4 Cohen AT, Alikhan R, Arcelus JI. et al. Assessment of venous thromboembolism risk and the benefits of thromboprophylaxis in medical patients. Thromb Haemost 2005; 94 (04) 750-759
    PubMedGoogle Scholar
  • 5 Samama MM. An epidemiologic study of risk factors for deep vein thrombosis in medical outpatients: the Sirius study. Arch Intern Med 2000; 160 (22) 3415-3420
    CrossrefPubMedGoogle Scholar
  • 6 Alikhan R, Cohen AT, Combe S. et al; MEDENOX Study. Risk factors for venous thromboembolism in hospitalized patients with acute medical illness: analysis of the MEDENOX Study. Arch Intern Med 2004; 164 (09) 963-968
    CrossrefPubMedGoogle Scholar
  • 7 Belch JJ, Lowe GD, Ward AG, Forbes CD, Prentice CR. Prevention of deep vein thrombosis in medical patients by low-dose heparin. Scott Med J 1981; 26 (02) 115-117
    CrossrefPubMedGoogle Scholar
  • 8 Samama MM, Cohen AT, Darmon JY. et al; Prophylaxis in Medical Patients with Enoxaparin Study Group. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med 1999; 341 (11) 793-800
    CrossrefPubMedGoogle Scholar
  • 9 Cohen AT, Davidson BL, Gallus AS. et al; ARTEMIS Investigators. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 2006; 332 (7537): 325-329
    CrossrefPubMedGoogle Scholar
  • 10 Flanders SA, Greene MT, Grant P. et al. Hospital performance for pharmacologic venous thromboembolism prophylaxis and rate of venous thromboembolism : a cohort study. JAMA Intern Med 2014; 174 (10) 1577-1584
    CrossrefPubMedGoogle Scholar
  • 11 Mahan CE, Fisher MD, Mills RM. et al. Thromboprophylaxis patterns, risk factors, and outcomes of care in the medically ill patient population. Thromb Res 2013; 132 (05) 520-526
    CrossrefPubMedGoogle Scholar
  • 12 Amin AN, Varker H, Princic N, Lin J, Thompson S, Johnston S. Duration of venous thromboembolism risk across a continuum in medically ill hospitalized patients. J Hosp Med 2012; 7 (03) 231-238
    CrossrefPubMedGoogle Scholar
  • 13 Hull RD, Schellong SM, Tapson VF. et al; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med 2010; 153 (01) 8-18
    CrossrefPubMedGoogle Scholar
  • 14 Goldhaber SZ, Leizorovicz A, Kakkar AK. et al; ADOPT Trial Investigators. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med 2011; 365 (23) 2167-2177
    CrossrefPubMedGoogle Scholar
  • 15 Cohen AT, Spiro TE, Büller HR. et al; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013; 368 (06) 513-523
    CrossrefPubMedGoogle Scholar
  • 16 Cohen AT, Harrington RA, Goldhaber SZ. et al; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med 2016; 375 (06) 534-544
    CrossrefPubMedGoogle Scholar
  • 17 Spyropoulos AC, Ageno W, Albers GW. et al; MARINER Investigators. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med 2018; 379 (12) 1118-1127
    CrossrefPubMedGoogle Scholar
  • 18 Bajaj NS, Vaduganathan M, Qamar A. et al. Extended prophylaxis for venous thromboembolism after hospitalization for medical illness: a trial sequential and cumulative meta-analysis. PLoS Med 2019; 16 (04) e1002797 DOI: 10.1371/journal.pmed.1002797.
    CrossrefPubMedGoogle Scholar
  • 19 Administration USFD. FDA approved betrixaban (BEVYXXA, Portola) for the prophylaxis of venous thromboembolism (VTE) in adult patients. June 23, 2007. Accessed September 2, 2020
    PubMedGoogle Scholar
  • 20 Johnson JPCoJ. U.S. FDA Approves XARELTO® (rivaroxaban) to help prevent blood clots in acutely ill medical patients. Accessed September 2, 2020
    PubMedGoogle Scholar
  • 21 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 (2, Suppl): e195S-e226S
    CrossrefPubMedGoogle Scholar
  • 22 Nicolaides AN, Fareed J, Kakkar AK. et al. Prevention and treatment of venous thromboembolism--International Consensus Statement. Int Angiol 2013; 32 (02) 111-260
    PubMedGoogle Scholar
  • 23 Schünemann HJ, Cushman M, Burnett 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
    CrossrefPubMedGoogle Scholar
  • 24 Spyropoulos AC, Anderson Jr FA, FitzGerald G. et al; IMPROVE Investigators. Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest 2011; 140 (03) 706-714
    CrossrefPubMedGoogle Scholar
  • 25 Chi G, Goldhaber SZ, Kittelson JM. et al. Effect of extended-duration thromboprophylaxis on venous thromboembolism and major bleeding among acutely ill hospitalized medical patients: a bivariate analysis. J Thromb Haemost 2017; 15 (10) 1913-1922
    CrossrefPubMedGoogle Scholar
  • 26 Spyropoulos AC, Lipardi C, Xu J. et al. Improved benefit risk profile of rivaroxaban in a subpopulation of the MAGELLAN Study. Clin Appl Thromb Hemost 2019; 25: 1076029619886022
    CrossrefPubMedGoogle Scholar
  • 27 Cohen AT, Spiro TE, Spyropoulos AC. et al; MAGELLAN Study Group. D-dimer as a predictor of venous thromboembolism in acutely ill, hospitalized patients: a subanalysis of the randomized controlled MAGELLAN trial. J Thromb Haemost 2014; 12 (04) 479-487
    CrossrefPubMedGoogle Scholar
  • 28 Gibson CM, Spyropoulos AC, Cohen AT. et al. The IMPROVEDD VTE Risk Score: incorporation of D-dimer into the improve score to improve venous thromboembolism risk stratification. TH Open 2017; 1 (01) e56-e65
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Spyropoulos AC, Lipardi C, Xu J. et al. Modified IMPROVE VTE Risk Score and Elevated D-dimer identify a high venous thromboembolism risk in acutely ill medical population for extended thromboprophylaxis. TH Open 2020; 4 (01) e59-e65
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Darzi AJ, Karam SG, Charide R. et al. Prognostic factors for VTE and bleeding in hospitalized medical patients: a systematic review and meta-analysis. Blood 2020; 135 (20) 1788-1810
    CrossrefPubMedGoogle Scholar
  • 31 Decousus H, Tapson VF, Bergmann JF. et al; IMPROVE Investigators. Factors at admission associated with bleeding risk in medical patients: findings from the IMPROVE investigators. Chest 2011; 139 (01) 69-79
    CrossrefPubMedGoogle Scholar
  • 32 Fhir H. SMART Application launch framework implementation guide release 1.0.0. http://www.hl7.org/fhir/smart-app-launch/ . Accessed Jan 14, 2021
    PubMedGoogle Scholar
  • 33 Kucher N, Koo S, Quiroz R. et al. Electronic alerts to prevent venous thromboembolism among hospitalized patients. N Engl J Med 2005; 352 (10) 969-977
    CrossrefPubMedGoogle Scholar
  • 34 Piazza G, Goldhaber SZ. Computerized decision support for the cardiovascular clinician: applications for venous thromboembolism prevention and beyond. Circulation 2009; 120 (12) 1133-1137
    CrossrefPubMedGoogle Scholar
  • 35 Piazza G, Anderson FA, Ortel TL. et al. Randomized trial of physician alerts for thromboprophylaxis after discharge. Am J Med 2013; 126 (05) 435-442
    CrossrefPubMedGoogle Scholar
  • 36 Cohoon KP, De Sanctis Y, Haskell L, McBane RD, Spiro TE. Rivaroxaban for thromboprophylaxis among patients recently hospitalized for acute infectious diseases: a subgroup analysis of the MAGELLAN study. J Thromb Haemost 2018; 16 (07) 1278-1287
    CrossrefPubMedGoogle Scholar
  • 37 Spyropoulos AC, Weitz JI. Hospitalized COVID-19 patients and venous thromboembolism: a perfect storm. Circulation 2020; 142 (02) 129-132
    CrossrefPubMedGoogle Scholar
  • 38 Obi AT, Tignanelli CJ, Jacobs BN. et al. Empirical systemic anticoagulation is associated with decreased venous thromboembolism in critically ill influenza A H1N1 acute respiratory distress syndrome patients. J Vasc Surg Venous Lymphat Disord 2019; 7 (03) 317-324
    CrossrefPubMedGoogle Scholar
  • 39 Bikdeli B, Madhavan MV, Jimenez D. et al; Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. COVID-19 and Thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review. J Am Coll Cardiol 2020; 75 (23) 2950-2973
    CrossrefPubMedGoogle Scholar
  • 40 Driggin E, Madhavan MV, Bikdeli B. et al. Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic. J Am Coll Cardiol 2020; 75 (18) 2352-2371
    CrossrefPubMedGoogle Scholar
  • 41 Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020; 18 (04) 844-847
    CrossrefPubMedGoogle Scholar
  • 42 Poissy J, Goutay J, Caplan M. et al; Lille ICU Haemostasis COVID-19 Group. Pulmonary embolism in patients with COVID-19: awareness of an increased prevalence. Circulation 2020; 142 (02) 184-186
    CrossrefPubMedGoogle Scholar
  • 43 Ren B, Yan F, Deng Z. et al. Extremely high incidence of lower extremity deep venous thrombosis in 48 patients with severe COVID-19 in Wuhan. Circulation 2020; 142 (02) 181-183
    CrossrefPubMedGoogle Scholar
  • 44 Martin AC, Huang W, Goldhaber SZ. et al. Estimation of acutely ill medical patients at venous thromboembolism risk eligible for extended thromboprophylaxis using APEX criteria in US hospitals. Clin Appl Thromb Hemost 2019; 25: 1076029619880008 DOI: 10.1177/1076029619880008.
    CrossrefPubMedGoogle Scholar
  • 45 Cohen AT. Extended thromboprophylaxis with betrixaban: a new standard for acute medically ill patients. Eur Heart J Suppl 2018; 20 (Suppl E): E1-E2
    CrossrefPubMedGoogle Scholar
  • 46 Owodunni OP, Lau BD, Streiff MB. et al. What the 2018 ASH venous thromboembolism guidelines omitted: nonadministration of pharmacologic prophylaxis in hospitalized patients. Blood Adv 2019; 3 (04) 596-598
    CrossrefPubMedGoogle Scholar