Association of D-dimer Levels with Clinical Event Rates and the Efficacy of Betrixaban versus Enoxaparin in the APEX Trial
05 September 2017
20 November 2017
08 January 2018 (online)
Background Elevated D-dimer concentrations are associated with an increased risk of venous thromboembolism (VTE). However, they may also provide prognostic value. The present analysis sought to study the association of D-dimer levels with VTE event rates and the efficacy of betrixaban versus enoxaparin in the APEX trial.
Methods Hospitalized acutely medically ill subjects (n = 7,513) were randomized in a double-dummy double-blind fashion to either extended-duration oral betrixaban (80 mg once daily for 35–42 days) or standard dose subcutaneous enoxaparin (40 mg once daily for 10 ± 4 days) for venous thromboprophylaxis. D-dimer was assessed using a central core laboratory measurement.
Results For every 0.25 µg/mL increase in D-dimer concentration, there was a 2% increase in the relative risk of experiencing the primary efficacy endpoint (asymptomatic deep vein thrombosis [DVT], symptomatic DVT, nonfatal pulmonary embolism, or VTE-related death) in both the betrixaban (p < 0.001) and enoxaparin (p < 0.001) treatment arms. Among D-dimer-positive (≥ 2 × upper limit of normal; corresponding to ≥ 1.00 µg/mL) subjects, extended-duration betrixaban reduced the risk of experiencing the primary efficacy outcome (5.4% [n = 124] vs. 7.6% [n = 170]; odds ratio = 0.69; 95% confidence interval: 0.55–0.88; absolute risk reduction = 2.2%, number needed to treat = 46, p = 0.003). There was no interaction between D-dimer and the treatment effect (p int = 0.53).
Conclusion Extended-duration betrixaban was superior to standard-duration enoxaparin, irrespective of D-dimer level at baseline. To prevent one VTE event, 46 D-dimer-positive patients would need to be treated with betrixaban.
- 1 Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, Melton III LJ. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000; 160 (06) 809-815
- 2 Douma RA, le Gal G, Söhne M. , et al. Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts. BMJ 2010; 340: c1475
- 3 Neuhaus J, Jacobs Jr DR, Baker JV. , et al. Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. J Infect Dis 2010; 201 (12) 1788-1795
- 4 Adam SS, Key NS, Greenberg CS. D-dimer antigen: current concepts and future prospects. Blood 2009; 113 (13) 2878-2887
- 5 Wells PS, Anderson DR, Rodger M. , et al. Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple clinical model and D-dimer. Ann Intern Med 2001; 135 (02) 98-107
- 6 Wells PS, Owen C, Doucette S, Fergusson D, Tran H. Does this patient have deep vein thrombosis?. JAMA 2006; 295 (02) 199-207
- 7 Halaby R, Popma CJ, Cohen A. , et al. D-Dimer elevation and adverse outcomes. J Thromb Thrombolysis 2015; 39 (01) 55-59
- 8 Becattini C, Lignani A, Masotti L, Forte MB, Agnelli G. D-dimer for risk stratification in patients with acute pulmonary embolism. J Thromb Thrombolysis 2012; 33 (01) 48-57
- 9 Knowlson L, Bacchu S, Paneesha S, McManus A, Randall K, Rose P. Elevated D-dimers are also a marker of underlying malignancy and increased mortality in the absence of venous thromboembolism. J Clin Pathol 2010; 63 (09) 818-822
- 10 Wen D, Du X, Dong JZ, Zhou XL, Ma CS. Value of D-dimer and C reactive protein in predicting inhospital death in acute aortic dissection. Heart 2013; 99 (16) 1192-1197
- 11 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
- 12 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
- 13 Desjardins L, Bara L, Boutitie F. , et al. Correlation of plasma coagulation parameters with thromboprophylaxis, patient characteristics, and outcome in the MEDENOX study. Arch Pathol Lab Med 2004; 128 (05) 519-526
- 14 Weber MA, Schiffrin EL, White WB. , et al. Clinical practice guidelines for the management of hypertension in the community a statement by the American Society of Hypertension and the International Society of Hypertension. J Hypertens 2014; 32 (01) 3-15
- 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
- 16 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
- 17 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 (06) 1240-1248
- 18 Boeer K, Siegmund R, Schmidt D, Deufel T, Kiehntopf M. Comparison of six D-dimer assays for the detection of clinically suspected deep venous thrombosis of the lower extremities. Blood Coagul Fibrinolysis 2009; 20 (02) 141-145