Asymptomatic Deep Vein Thrombosis is Associated with an Increased Risk of Death: Insights from the APEX Trial

Arzu Kalayci; C. Michael Gibson; Gerald Chi; Megan K. Yee; Serge Korjian; Sudarshana Datta; Tarek Nafee; Mike Gurin; Noah Haroian; Iqra Qamar; Russell D. Hull; Adrian F. Hernandez; Alexander T. Cohen; Robert A. Harrington; Samuel Z. Goldhaber

doi:10.1055/s-0038-1675606

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2018; 118(12): 2046-2052
DOI: 10.1055/s-0038-1675606

Coagulation and Fibrinolysis

Georg Thieme Verlag KG Stuttgart · New York

Asymptomatic Deep Vein Thrombosis is Associated with an Increased Risk of Death: Insights from the APEX Trial

Arzu Kalayci

¹Division of Cardiovascular, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States

,

C. Michael Gibson

¹Division of Cardiovascular, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States

,

Gerald Chi

¹Division of Cardiovascular, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States

,

Megan K. Yee

¹Division of Cardiovascular, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States

,

Serge Korjian

¹Division of Cardiovascular, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States

,

Sudarshana Datta

¹Division of Cardiovascular, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States

,

Tarek Nafee

¹Division of Cardiovascular, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States

,

Mike Gurin

¹Division of Cardiovascular, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States

,

Noah Haroian

¹Division of Cardiovascular, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States

,

Iqra Qamar

¹Division of Cardiovascular, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States

,

Russell D. Hull

²Division of Cardiology, R.A.H Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada

,

Adrian F. Hernandez

³ Duke Clinical Research Institute, Durham, North Carolina, United States

,

Alexander T. Cohen

⁴Department of Haematological Medicine, Guy's and St Thomas' Hospitals, King's College, London, United Kingdom

,

Robert A. Harrington

⁵Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, California, United States

,

Samuel Z. Goldhaber

⁶Division of Cardiovascular, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States

› Author Affiliations

Abstract

Aim Asymptomatic deep vein thrombosis (DVT) diagnosed with compression ultrasound (CUS) is a common endpoint in trials assessing the efficacy of anticoagulants to prevent venous thromboembolism (VTE), but the relationship of asymptomatic thrombus to mortality remains uncertain.

Methods In the APEX trial (ClinicalTrials.gov: NCT01583218), 7,513 acutely ill hospitalized medical patients were randomly assigned to extended-duration betrixaban (35–42 days) or enoxaparin (10 ± 4 days). Asymptomatic DVT was assessed once with CUS between day 32 and 47, and mortality was assessed through 77 days.

Results A total of 309 asymptomatic DVTs were detected through CUS. Of these, 133 (4.27%) subjects were in the betrixaban group, and 176 (5.55%) subjects were in the enoxaparin group (relative risk = 0.77, 95% confidence interval [CI] = 0.62–0.97, p = 0.025, number needed to treat = 79). With respect to all-cause mortality due to cardiovascular diseases, non-cardiovascular diseases and unknown causes, the number of the deaths was 5 (1.67%), 4 (1.34%) and 1 (0.33%) in the asymptomatic DVT group and 25 (0.42%), 33 (0.56%) and 11 (0.19%) in the no DVT group, respectively. Subjects with an asymptomatic DVT had an almost threefold increase in the risk of all-cause mortality compared with subjects without DVT (hazard ratio = 2.87, 95% CI = 1.48–5.57, p = 0.001). A positive linear trend was observed between greater thrombus burden and mortality during the follow-up (p = 0.019).

Conclusion Asymptomatic DVT was associated with approximately threefold increased risk of short-term all-cause mortality in patients hospitalized with an acute medical illness within the prior 77 days. A positive linear trend was observed between greater thrombus burden and mortality during the follow-up.

Keywords

venous thrombosis - asymptomatic deep vein thrombosis - betrixaban - acute medical illness

Full Text

References

References
1 Piazza G, Fanikos J, Zayaruzny M, Goldhaber SZ. Venous thromboembolic events in hospitalised medical patients. Thromb Haemost 2009; 102 (03) 505-510
2 Cohen AT, Agnelli G, Anderson FA. , et al; VTE Impact Assessment Group in Europe (VITAE). Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost 2007; 98 (04) 756-764
3 Cohen AT, Tapson VF, Bergmann JF. , et al; ENDORSE Investigators. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet 2008; 371 (9610): 387-394
4 Heit JA. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol 2008; 28 (03) 370-372
5 Lloyd NS, Douketis JD, Moinuddin I, Lim W, Crowther MA. Anticoagulant prophylaxis to prevent asymptomatic deep vein thrombosis in hospitalized medical patients: a systematic review and meta-analysis. J Thromb Haemost 2008; 6 (03) 405-414
6 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
7 Cohen AT, Harrington R, Goldhaber SZ. , et al. The design and rationale for the Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban (APEX) study. Am Heart J 2014; 167 (03) 335-341
8 Chi G, Goldhaber SZ, Hull RD. , et al. Thrombus burden of deep vein thrombosis and its association with thromboprophylaxis and D-dimer measurement: insights from the APEX trial. Thromb Haemost 2017; 117 (12) 2389-2395
9 Heit JA, O'Fallon WM, Petterson TM. , et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch Intern Med 2002; 162 (11) 1245-1248
10 Moser KM, LeMoine JR. Is embolic risk conditioned by location of deep venous thrombosis?. Ann Intern Med 1981; 94 (4 pt 1): 439-444
11 Dean SM, Abraham W. Venous thromboembolic disease in congestive heart failure. Congest Heart Fail 2010; 16 (04) 164-169
12 Poredos P, Jezovnik MK. The role of inflammation in venous thromboembolism and the link between arterial and venous thrombosis. Int Angiol 2007; 26 (04) 306-311
13 Lee AY, Levine MN. Venous thromboembolism and cancer: risks and outcomes. Circulation 2003; 107 (23) (Suppl. 01) I17-I21
14 Kelly J, Rudd A, Lewis R, Hunt BJ. Venous thromboembolism after acute stroke. Stroke 2001; 32 (01) 262-267
15 Landi G, D'Angelo A, Boccardi E. , et al. Venous thromboembolism in acute stroke. Prognostic importance of hypercoagulability. Arch Neurol 1992; 49 (03) 279-283
16 Cope C, Reyes TM, Skversky NJ. Phlebographic analysis of the incidence of thrombosis in hemiplegia. Radiology 1973; 109 (03) 581-584
17 Vaitkus PT, Leizorovicz A, Cohen AT, Turpie AG, Olsson CG, Goldhaber SZ. ; PREVENT Medical Thromboprophylaxis Study Group. Mortality rates and risk factors for asymptomatic deep vein thrombosis in medical patients. Thromb Haemost 2005; 93 (01) 76-79
18 Spyropoulos AC, Raskob GE. New paradigms in venous thromboprophylaxis of medically ill patients. Thromb Haemost 2017; 117 (09) 1662-1670
19 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
20 Turpie AG, Hull RD, Schellong SM. , et al; EXCLAIM Investigators. Venous thromboembolism risk in ischemic stroke patients receiving extended-duration enoxaparin prophylaxis: results from the EXCLAIM study. Stroke 2013; 44 (01) 249-251
21 Berger J, Eikelboom JW, Quinlan DJ. , et al. Venous thromboembolism prophylaxis: do trial results enable clinicians and patients to evaluate whether the benefits justify the risk? Proceedings of an Ad Hoc Working Group Meeting. J Thromb Haemost 2013; 11 (04) 778-782
22 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
23 Hull RD, Marder VJ, Mah AF, Biel RK, Brant RF. Quantitative assessment of thrombus burden predicts the outcome of treatment for venous thrombosis: a systematic review. Am J Med 2005; 118 (05) 456-464