Thrombus Burden of Deep Vein Thrombosis and Its Association with Thromboprophylaxis and D-Dimer Measurement: Insights from the APEX Trial

Abstract

Background The aim of this study was to evaluate the effect of betrixaban on the occurrence of deep vein thrombosis (DVT) and also the extent of thrombus and to assess the association of baseline D-dimer with subsequent thrombus burden.

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). D-dimer concentration was measured at baseline, and mandatory lower-extremity compression ultrasonography (CUS) was performed at 35 to 42 days. The thrombus burden of DVT was assessed by the number of non-compressible vascular segments in six target proximal veins and compared between treatment groups and D-dimer categories (≥2 × upper limit of normal [ULN] versus <2 × ULN).

Results Compared with enoxaparin, extended-duration betrixaban reduced the DVT risk at 35 to 42 days (any-dose: relative risk [RR] = 0.76 [95% confidence interval: 0.61–0.94]; p = 0.013; full-dose: RR = 0.70 [0.55–0.90]; p = 0.005). Patients who received betrixaban were more likely to have a lower thrombus burden (p = 0.012 for any-dose and p = 0.001 for full-dose). Elevated D-dimer at baseline was independently associated with a 2.12-fold increased risk of developing DVT (p < 0.001). A greater thrombus burden was also observed in those with D-dimer ≥ 2 × ULN compared with <2 × ULN (p < 0.0001).

Conclusion Extended-duration betrixaban reduced the number of venous segments with thrombosis at 35 to 42 days compared with enoxaparin. A positive D-dimer was associated with a greater extent of thrombus burden among acutely ill medical patients who developed DVT despite receiving thromboprophylaxis.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. ClinicalTrials.gov identifier: NCT01583218.

Keywords

venous thrombosis - venous thromboembolism - D-dimer - anticoagulants - factor Xa inhibitors

• References

• 1 Heit JA, Crusan DJ, Ashrani AA, Petterson TM, Bailey KR. Effect of a near-universal hospitalization-based prophylaxis regimen on annual number of venous thromboembolism events in the US. Blood 2017; 130 (02) 109-114
• 2 Saha P, Humphries J, Modarai B. , et al. Leukocytes and the natural history of deep vein thrombosis: current concepts and future directions. Arterioscler Thromb Vasc Biol 2011; 31 (03) 506-512
• 3 Halaby R, Popma CJ, Cohen A. , et al. D-Dimer elevation and adverse outcomes. J Thromb Thrombolysis 2015; 39 (01) 55-59
• 4 Spyropoulos AC, Raskob GE. New paradigms in venous thromboprophylaxis of medically ill patients. Thromb Haemost 2017; 117 (09) 1662-1670
• 5 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
• 6 Kearon C. Natural history of venous thromboembolism. Circulation 2003; 107 (23) (Suppl. 01) I22-I30
• 7 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
• 8 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
• 9 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
• 10 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
• 11 Tan M, Mos IC, Klok FA, Huisman MV. Residual venous thrombosis as predictive factor for recurrent venous thromboembolim in patients with proximal deep vein thrombosis: a sytematic review. Br J Haematol 2011; 153 (02) 168-178
• 12 Palareti G. How I treat isolated distal deep vein thrombosis (IDDVT). Blood 2014; 123 (12) 1802-1809
• 13 Palareti G, Schellong S. Isolated distal deep vein thrombosis: what we know and what we are doing. J Thromb Haemost 2012; 10 (01) 11-19
• 14 Monreal M, Ruíz J, Olazabal A, Arias A, Roca J. Deep venous thrombosis and the risk of pulmonary embolism. A systematic study. Chest 1992; 102 (03) 677-681
• 15 Righini M. Is it worth diagnosing and treating distal deep vein thrombosis? No. J Thromb Haemost 2007; 5 (Suppl. 01) 55-59
• 16 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
• 17 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
• 18 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
• 19 Lippi G, Tripodi A, Simundic AM, Favaloro EJ. International survey on D-dimer test reporting: a call for standardization. Semin Thromb Hemost 2015; 41 (03) 287-293