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Clinical Trial
. 2013 Feb;160(4):530-7.
doi: 10.1111/bjh.12163. Epub 2012 Dec 13.

Prediction and prevention of thromboembolic events with enoxaparin in cancer patients with elevated tissue factor-bearing microparticles: a randomized-controlled phase II trial (the Microtec study)

Jeffrey I Zwicker  1 , Howard A Liebman, Kenneth A Bauer, Thomas Caughey, Federico Campigotto, Rachel Rosovsky, Simon Mantha, Craig M Kessler, Jonathan Eneman, Vidya Raghavan, Heinz-Joseph Lenz, Andrea Bullock, Elizabeth Buchbinder, Donna Neuberg, Bruce Furie
Affiliations
Clinical Trial

Prediction and prevention of thromboembolic events with enoxaparin in cancer patients with elevated tissue factor-bearing microparticles: a randomized-controlled phase II trial (the Microtec study)

Jeffrey I Zwicker et al. Br J Haematol. 2013 Feb.

Abstract

Elevated levels of circulating tissue factor-bearing microparticles (TFMP) have been associated with an increased risk of developing venous thromboembolism (VTE) in cancer patients. We performed a randomized phase II study to evaluate the cumulative incidence of VTE in advanced cancer patients with lower levels of TFMP not receiving thromboprophylaxis and those with higher levels of circulating TFMP randomized to enoxaparin or observation. The cumulative incidence of VTE at 2 months in the higher TFMP group randomized to enoxaparin (N = 23) was 5·6% while the higher TFMP group observation arm (N = 11) was 27·3% (Gray test P = 0·06). The cumulative incidence of VTE in the low TFMP was 7·2% (N = 32). No major haemorrhages were observed in the enoxaparin arm. The median survival for patients with higher levels of TFMP followed by observation was 11·8 months compared with 17·8 months on enoxaparin (P = 0·58). In a prospective randomized trial, increased numbers of circulating TFMP detected by impedance flow cytometry identified cancer patients with a high incidence of VTE. Enoxaparin demonstrated a clear trend towards reducing the rate of VTE in patients with elevated levels of TFMP, with an overall rate of VTE similar in magnitude to the lower TFMP group.

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Conflict of interest statement

Conflict-of-interest disclosure: HAL has served on steering committees for Sanofi; CMK has received research funds and served on advisory boards for Sanofi and Esai. No other authors report relevant conflicts-of-interest.

Figures

Figure 1
Figure 1. MicroTEC trial schema
The plasma concentration of tissue factor-bearing microparticles (TFMP) was measured following enrollment. Individuals with higher concentrations of tissue factor-bearing microparticles were randomized 2:1 to enoxaparin 40 mg daily versus observation. Individuals with low tissue factor-bearing microparticles were followed without anticoagulation. Study subjects were scheduled to undergo lower extremity ultrasound on Day 1 and Day 60 to evaluate for an incidental proximal deep vein thrombosis.
Figure 2
Figure 2. Flow diagram of MicroTEC enrollment
A total of 70 patients were enrolled in the trial with data available for primary endpoint venous thromboembolism (VTE) analysis in 66 patients (34 with high levels of tissue factor-bearing microparticles (TFMP) and 32 with lower levels of tissue factor-bearing microparticles).
Figure 3
Figure 3. Cumulative incidence of venous thromboembolism with higher or lower concentration of tissue factor-bearing microparticles
The cumulative incidence of venous thromboembolism (VTE) at 2 months in the group of patients with higher levels of tissue factor-bearing microparticles randomized to observation was 27.2% (blue) compared with 5.6% (green) in the group treated with enoxaparin (Gray test P value =0.06). The cumulative incidence of VTE at 2-months for the cohort with lower levels of tissue factor-bearing microparticles was 7.2% (red).
Figure 4
Figure 4. Overall survival based on tissue factor-bearing microparticle status
Median survival for study subjects with higher concentration of tissue factor-bearing microparticles (TFMP) on observation (blue) was 11.8 months compared with 17.8 months on enoxaparin (green, Log-rank test P-value=0.58). The median survival for lower tissue factor-bearing microparticle arm was 17.3 months (red).
Figure 5
Figure 5. Correlation between concentration of tissue factor-bearing microparticles and D-dimer with VTE
a) Baseline concentration of tissue factor-bearing microparticles did not correlate with D-dimer values (Spearman coefficient 0.10). Dark triangles represent subjects randomized to enoxaparin and open triangles represent subjects followed without anticoagulation. The open circles represent subjects diagnosed with a VTE primary endpoint (including a study subject diagnosed with VTE prior to randomization). b) Cumulative incidence of VTE for subjects with very elevated D-dimer values (>1500 μg/l) and higher tissue factor-bearing microparticles (N=12, dashed line) compared with all other study subjects (N=55, Gray’s test P value=0.0001, solid line).
Figure 5
Figure 5. Correlation between concentration of tissue factor-bearing microparticles and D-dimer with VTE
a) Baseline concentration of tissue factor-bearing microparticles did not correlate with D-dimer values (Spearman coefficient 0.10). Dark triangles represent subjects randomized to enoxaparin and open triangles represent subjects followed without anticoagulation. The open circles represent subjects diagnosed with a VTE primary endpoint (including a study subject diagnosed with VTE prior to randomization). b) Cumulative incidence of VTE for subjects with very elevated D-dimer values (>1500 μg/l) and higher tissue factor-bearing microparticles (N=12, dashed line) compared with all other study subjects (N=55, Gray’s test P value=0.0001, solid line).
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