New paradigms in venous thromboprophylaxis of medically ill patients

Alex C. Spyropoulos; Gary E. Raskob

doi:10.1160/TH17-03-0168

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2017; 117(09): 1662-1670
DOI: 10.1160/TH17-03-0168

Invited Clinical Focus

Schattauer GmbH

New paradigms in venous thromboprophylaxis of medically ill patients

Alex C. Spyropoulos

¹Hofstra Northwell School of Medicine, Department of Medicine, Anticoagulation and Clinical Thrombosis Services, Northwell Health System at Lenox Hill Hospital, New York, New York, USA

,

Gary E. Raskob

²College of Public Health,University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

› Author Affiliations

Abstract

Summary

Acutelly-ill hospitalised medical patients are at risk of venous thromboembolism (VTE), both in-hospital and in the immediate post-discharge period, and mortality from VTE is thought to be particularly high in this patient population. However, despite previous mandates from international antithrombotic guidelines such as those of the American College of Chest Physicians (ACCP) for the “universal” use of thromboprophylaxis in hospitalised medical patients, global audits suggest that implementation of thromboprophylaxis continues to be challenging because of the perceived higher risk of bleeding and lower risk of VTE than that reported in clinical trials. Recent population-based studies also reveal that a “universal” hospital-only thromboprophylactic strategy does not reduce the community burden of VTE from this population, which may constitute nearly one quarter of the attributable risk of VTE. Lastly, four large randomised placebo-controlled trials of extended thromboprophylaxis have failed to show a definitive net clinical benefit in hospitalised medical patients. Recent large-scale efforts in deriving and validating scored VTE and bleed risk assessment models (RAMs) have been completed in the medically-ill population. In addition, an elevated D-dimer as a new biomarker to identify at-VTE risk medically ill patients has also undergone prospective evaluation. This paper will review current concepts of VTE and bleed risk in hospitalised medical patients, both in the hospital as well as the post-hospital discharge period, and will discuss new paradigms of thromboprophylaxis in this population using an individualised, patient-centered approach.

Keywords

Medical patient - risk assessment models - d-dimer - venous thromboembolism - bleeding - thromboprophylaxis - Padua Score - NHS Tool - IMPROVE Score - low-molecular-weight heparin - direct oral anticoagulants

Full Text

References

References
1 Anderson FA, Zayaruzny M, Heit JA. et al. Estimated annual numbers of US acute-care hospital patients at risk for venous thromboembolism. Am J Hematol 2007; 82: 777-782.
2 Cohen AT, Agnelli G, Anderson FA. et al. Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost 2007; 98: 756-764.
3 Heit JA. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol 2008; 28: 370-372.
4 Spyropoulos AC, Anderson FA, Fitzgerald G. et al. Predictive and associative models to identify hospitalised medical patients at risk for VTE. Chest 2011; 140: 706-714.
5 Geerts WH, Heit JA, Clagett GP. et al. Prevention of venous thromboembolism. Chest 2001; 119 (Suppl. 01) 132S-175S.
6 Spyropoulos AC. Emerging strategies in the prevention of venous thromboembolism in hospitalised medical patients. Chest 2005; 128: 958-969.
7 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. 06) 381S-453S.
8 Kleber FX, Witt C, Vogel G. et al. Randomized comparison of enoxaparin with unfractionated heparin for the prevention of venous thromboembolism in medical patients with heart failure or severe respiratory disease. Am Heart J 2003; 145: 614-621.
9 Alikhan R, Cohen AT, Combe S. et al. Risk factors for venous thromboembolism in hospitalised patients with acute medical illness: analysis of the MEDENOX Study. Arch Intern Med 2004; 164: 963-968.
10 Cohen AT, Tapson VF, Bergmann JF. et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet 2008; 371: 387-394.
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: 520-526.
12 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: 1577-1584.
13 Liew AY, Piran S, Eikelboom JW, Douketis JD. Extended-duration versus short-duration pharmacological thromboprophylaxis in acutely Ill hospitalised medical patients: a systematic review and meta-analysis of randomized controlled trials. J Thromb Thrombolysis 2017; 43: 291-301.
14 Dentali F, Mumoli N, Prisco D. et al. Efficacy and safety of extended thrombo-prophylaxis for medically ill patients. A meta-analysis of randomised controlled trials. Thromb Haemost 2017; 117: 606-617.
15 Anderson FA, Wheeler HB, Goldberg RJ. et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151: 933-938.
16 Huang W, Anderson FA, Spencer FA. et al. Risk-assessment models for predicting venous thromboembolism among hospitalised non-surgical patients: a systematic review. J Thromb Thrombolysis 2013; 35: 67-80.
17 Spyropoulos AC, McGinn T, Khorana AA. The use of weighted and scored risk assessment models for venous thromboembolism. Thromb Haemost 2012; 108: 1072-1076.
18 Cade JF. High risk of the critically ill for venous thromboembolism. Crit Care Med 1982; 10: 448-450.
19 Belch JJ, Lowe GD, Ward AG. et al. Prevention of deep vein thrombosis in medical patients by low-dose heparin. Scott Med J 1981; 26: 115-117.
20 Nicolaides AN, Breddin HK, Fareed J. et al. Prevention of venous thromboembolism. International Consensus Statement. Guidelines compiled in accordance with the scientific evidence. Int Angiol 2001; 20: 1-37.
21 Enders JM, Burke JM, Dobesh PP. Prevention of venous thromboembolism in acute medical illness. Pharmacotherapy 2002; 22: 1564-1578.
22 Sandler DA, Martin JF. Autopsy proven pulmonary embolism in hospital patients: are we detecting enough deep vein thrombosis?. J R Soc Med 1989; 82: 203-205.
23 Baglin TP, White K, Charles A. Fatal pulmonary embolism in hospitalised medical patients. J Clin Pathol 1997; 50: 609-610.
24 Sperry KL, Key CR, Anderson RE. Toward a population-based assessment of death due to pulmonary embolism in New Mexico. Hum Pathol 1990; 21: 159-165.
25 Hauch O, Jørgensen LN, Khattar SC. et al. Fatal pulmonary embolism associated with surgery. An autopsy study. Acta Chir Scand 1990; 156: 747-749.
26 Cohen AT, Edmondson RA, Phillips MJ. et al. The changing pattern of venous thromboembolic disease. Haemostasis 1996; 26: 65-71.
27 Halkin H, Goldberg J, Modan M, Modan B. Reduction of mortality in general medical in-patients by low-dose heparin prophylaxis. Ann Intern Med 1982; 96: 561-565.
28 Gärdlund B. Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. The Heparin Prophylaxis Study Group. Lancet 1996; 347: 1357-1361.
29 Samama MM, Cohen AT, Darmon JY. et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 1999; 341: 793-800.
30 Leizorovicz A, Cohen AT, Turpie AG. et al. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation 2004; 110: 874-879.
31 Cohen AT, Davidson BL, Gallus AS. et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. Br Med J 2006; 332: 325-329.
32 Dentali F, Douketis JD, Gianni M. et al. Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalised medical patients. Ann Intern Med 2007; 146: 278-288.
33 Hull RD, Merali T, Mills A. et al. Venous thromboembolism in elderly high-risk medical patients: time course of events and influence of risk factors. Clin Appl Thromb Hemost 2013; 19: 357-362.
34 Hull RD, Schellong SM, Tapson VF. et al. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med 2010; 153: 8-18.
35 Cohen AT, Spiro TE, Büller HR. et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013; 368: 513-523.
36 Goldhaber SZ, Leizorovicz A, Kakkar AK. et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med 2011; 365: 2167-2177.
37 Cohen AT, Harrington RA, Goldhaber SZ. et al. Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients. N Engl J Med 2016; 375: 534-544.
38 Liew AY, Piran S, Eikelboom JW, Douketis JD. Extended-duration versus short-duration pharmacological thromboprophylaxis in acutely Ill hospitalised medical patients: a systematic review and meta-analysis of randomized controlled trials. J Thromb Thrombolysis. 2016 Epub ahead of print
39 Guyatt GH, Eikelboom JW, Gould MK. et al. Approach to outcome measurement in the prevention of thrombosis in surgical and medical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl. 02) e185S-194S.
40 Cabana MD, Rand CS, Powe NR. et al. Why don’t physicians follow clinical practice guidelines? A framework for improvement. J Am Med Assoc 1999; 282: 1458-1465.
41 Bergmann JF, Mouly S. Thromboprophylaxis in medical patients: focus on France. Semin Thromb Hemost 2002; 28 Suppl 03 51-55.
42 Carrier M, Khorana AA, Moretto P. et al. Lack of evidence to support thrombo-prophylaxis in hospitalised medical patients with cancer. Am J Med 2014; 127: 82-86. e1.
43 Spencer A, Cawood T, Frampton C. et al. Heparin-based treatment to prevent symptomatic deep venous thrombosis, pulmonary embolism or death in general medical inpatients is not supported by best evidence. Intern Med J 2014; 44: 1054-1065.
44 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. 02) e195S-226S.
45 Barbar S, Noventa F, Rossetto V. et al. A risk assessment model for the identification of hospitalised medical patients at risk for venous thromboembolism: the Padua Prediction Score. J Thromb Haemost 2010; 08: 2450-2457.
46 Greene MT, Spyropoulos AC, Chopra V. et al. Validation of Risk Assessment Models of Venous Thromboembolism in Hospitalised Medical Patients. Am J Med 2016; 129: 1001 e9-.e18
47 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: 692-699.
48 Rosenberg D, Eichorn A, Alarcon M. et al. 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; 03: e001152
49 Lester W, Freemantle N, Begaj I. et al. Fatal venous thromboembolism associated with hospital admission: a cohort study to assess the impact of a national risk assessment target. Heart 2013; 99: 1734-1739.
50 Tapson VF, Decousus H, Pini M. et al. Venous thromboembolism prophylaxis in acutely ill hospitalised medical patients: findings from the International Medical Prevention Registry on Venous Thromboembolism. Chest 2007; 132: 936-945.
51 Nendaz M, Spirk D, Kucher N. et al. Multicentre validation of the Geneva Risk Score for hospitalised medical patients at risk of venous thromboembolism. Explicit ASsessment of Thromboembolic RIsk and Prophylaxis for Medical PATients in SwitzErland (ESTIMATE). Thromb Haemost 2014; 111: 531-538.
52 Amin A, Spyropoulos AC, Dobesh P. et al. Are hospitals delivering appropriate VTE prevention? The venous thromboembolism study to assess the rate of thromboprophylaxis (VTE start). J Thromb Thrombolysis 2010; 29: 326-339.
53 Decousus H, Tapson VF, Bergmann JF. et al. Factors at admission associated with bleeding risk in medical patients: findings from the IMPROVE investigators. Chest 2011; 139: 69-79.
54 Rosenberg DJ, Press A, Fishbein J. et al. External validation of the IMPROVE Bleeding Risk Assessment Model in medical patients. Thromb Haemost 2016; 116: 530-536.
55 Day ISCfWT. Venous thromboembolism: A Call for risk assessment in all hospitalised patients. Thromb Haemost 2016; 116: 777-779.
56 Health Do. Venous Thromboembolism (VTE) Risk Assessment. 2010 Available from: https://dh.gov.uk/en/Publicationsandstatistics/ . Available from: https://www.jointcommission.org/assets/1/6/HIQR_SpecsManual_v52a.zip
57 Adam SS, Key NS, Greenberg CS. D-dimer antigen: current concepts and future prospects. Blood 2009; 113: 2878-2887.
58 Cohen AT, Spiro TE, Spyropoulos AC. et al. D-dimer as a predictor of venous thromboembolism in acutely ill, hospitalised patients: a subanalysis of the randomized controlled MAGELLAN trial. J Thromb Haemost 2014; 12: 479-487.
59 Mebazaa A, Spiro TE, Büller HR. et al. Predicting the risk of venous thromboembolism in patients hospitalised with heart failure. Circulation 2014; 130: 410-418.
60 Gibson CMCG, Jain P, Szlosek D. et al. IMPROVEDD Score: Addition of D-Dimer to the IMPROVE Score Improves Venous Thromboembolism Risk Stratification. An APEX Trial Substudy. Circulation 2016; 134: A19875
61 Raskob GE, Spyropoulos AC, Zrubek J. et al. The MARINER trial of rivaroxaban after hospital discharge for medical patients at high risk of VTE. Design, rationale, and clinical implications. Thromb Haemost 2016; 115: 1240-1248.
62 Squizzato A, Ageno W. A new era for venous thromboembolism prevention in medical inpatients. Thromb Haemost 2014; 112: 627-628.