Abstract

Background: Elevated levels of coagulation markers such as D-dimer, prothrombin fragment 1+2 (F1+2), and thrombin antithrombin (TAT) have been associated with increased risk for thrombotic events. Apixaban, an oral, selective, direct inhibitor of factor Xa, was shown to be effective for the prevention and treatment of venous thromboembolism (VTE). Apixaban is also in development for stroke prevention in atrial fibrillation patients and secondary prevention in patients with acutre coronary syndrome. This study was conducted to assess changes in coagulation biomarkers after apixaban treatment.

Methods: Approximately 1430 plasma samples (pre-dose, week 3 and week 12) were obtained from 520 patients who participated in a phase 2, randomized, parallel-arm, double-blind study of apixaban for the treatment of acute symptomatic deep-vein thrombosis. The study comprised 4 dose arms of approximately 130 patients each (apixaban 5 mg bid, 10 mg bid, 20 mg qd, and 1 active control arm, low molecular weight heparin [LMWH] followed by vitamin K antagonist [VKA] [target INR 2–3]). Five biomarkers, D-dimer, F1+2, TAT, modified prothrombin time (mPT), and anti-Xa activity were measured in plasma. Biomarker responses over treatment time were evaluated using an ANOVA mixed-effect model.

Results: Biomarkers of thrombin generation and fibrin turnover, D-dimer, F1+2, and TAT, were significantly elevated at the time of trial randomization in all dose groups with approximately 95%, 46%, and 43% of patients showing values above the upper limit of normal range (ULN) for D-dimer, F1+2, and TAT values, respectively. The respective median biomarker values were 1662 ng/mL, 294 pmol/L, and 4.1 ng/mL. After 3 and 12 weeks of drug treatment, the biomarker values were significantly reduced in the majority of patients in all dose groups (Table). By the end of 12 weeks, the number of patients who continued to have marker values exceeding the ULN in the 4 dose groups ranged from 24% to 40%, 8% to 13%, and 7% to 12%, for D-dimer, F1+2, and TAT, respectively. Pharmacodynamic biomarkers mPT and anti-Xa activity increased with increasing apixaban exposure (R2 = 0.534 for mPT and 0.853 for anti-Xa activity). When comparing the accuracy and precision of mPT and anti-Xa assays in predicting apixaban plasma concentration, the difference between predicted and observed apixaban concentration was much lower for the anti-Xa assay compared to mPT. The median absolute error of the anti-Xa assay was 12% compared with 48% for mPT.

Conclusion: 12 weeks of apixaban treatment results in pronounced reduction of coagulation activity as measured by D-dimer, F1+2, and TAT, which is consistent with the low number of thrombotic events observed in apixaban-treated patients in this study (symptomatic VTE rate of 2.5% in the combined apixaban group and the comparator group). The anti-Xa assay demonstrated very good accuracy and precision in predicting apixaban plasma concentration in this clinical trial.

Table

 D-dimer (% Patients > ULN) F1+2 (% Patients > ULN) TAT (% Patients > ULN) 
Treatment Groups Predose Week 3 Week 12 Predose Week 3 Week 12 Predose Week 3 Week 12 
Apixaban 5 mg bid 93% 75% 32% 43% 19% 13% 36% 13% 12% 
Apixaban 10 mg bid 100% 74% 31% 41% 12% 8% 44% 7% 7% 
Apixaban 20 mg qd 93% 74% 40% 46% 21% 16% 43% 16% 12% 
LMWH/VKA 98% 72% 24% 54% 10% 10% 48% 11% 9% 
 D-dimer (% Patients > ULN) F1+2 (% Patients > ULN) TAT (% Patients > ULN) 
Treatment Groups Predose Week 3 Week 12 Predose Week 3 Week 12 Predose Week 3 Week 12 
Apixaban 5 mg bid 93% 75% 32% 43% 19% 13% 36% 13% 12% 
Apixaban 10 mg bid 100% 74% 31% 41% 12% 8% 44% 7% 7% 
Apixaban 20 mg qd 93% 74% 40% 46% 21% 16% 43% 16% 12% 
LMWH/VKA 98% 72% 24% 54% 10% 10% 48% 11% 9% 

Disclosures: No relevant conflicts of interest to declare.

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