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Rivaroxaban and apixaban in orthopaedics: is there a difference in their plasma concentrations and anticoagulant effects?

Freyburger G, Macouillard G, Khennoufa K, Labrouche S, Molimard M, Sztark F - Blood Coagul. Fibrinolysis (2015)

Bottom Line: After 1 week of treatment, the drugs differed: Cmax and Ctrough were closer when apixaban was taken twice daily (83 ± 39 and 58 ± 17 ng/ml) than with rivaroxaban taken once a day (113 ± 67 and 13 ± 20 ng/ml).Rivaroxaban had a greater influence on routine coagulation tests and reduced the maximum thrombin concentration more efficiently, as assessed by the thrombin generation test.Although rivaroxaban and apixaban present apparently similar constant rates, they exhibit significant differences in their concentrations and anticoagulant effects when studied ex vivo in orthopedic patients.

View Article: PubMed Central - PubMed

Affiliation: aLaboratory of Hematology bDepartment of Anesthesiology cLaboratory of Clinical Pharmacology, Bordeaux University Hospital, Bordeaux, France.

ABSTRACT
The aim of this study was to improve knowledge of what happens in the coagulation of orthopaedic patients under rivaroxaban and apixaban, in order to finalize and cross-validate effective measurement methods and to provide arguments for helping to reference one or the other drug in our central pharmacy. One hundred and two patients undergoing total hip or knee replacement were included. Half of them received rivaroxaban and the other half received apixaban. Blood samples (n = 244 with each drug) were taken at Cmax preoperatively and twice a week, apart from the day of the patient's discharge, when Ctrough concentration was targeted. Routine coagulation parameters, and functional and liquid chromatography tandem mass spectrometry assays for measurement of circulating concentrations were studied. The LC-MS/MS assay and the functional assays carried out in patients under routine conditions were highly correlated, apart from low concentrations (<30 ng/ml), which were affected by the variable individual potential to inhibit the exogenous bovine Xa used in the functional assays. After 1 week of treatment, the drugs differed: Cmax and Ctrough were closer when apixaban was taken twice daily (83 ± 39 and 58 ± 17 ng/ml) than with rivaroxaban taken once a day (113 ± 67 and 13 ± 20 ng/ml). Rivaroxaban had a greater influence on routine coagulation tests and reduced the maximum thrombin concentration more efficiently, as assessed by the thrombin generation test. Although rivaroxaban and apixaban present apparently similar constant rates, they exhibit significant differences in their concentrations and anticoagulant effects when studied ex vivo in orthopedic patients.

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Thrombin generation test curves showing the concentration of thrombin (in nmol/l, Y-axis) according to the time (min, X-axis) after stimulation by a low concentration of tissue factor in the presence of phospholipids. The two upper graphs represent rivaroxaban-treated samples and the two lower graphs represent apixaban-treated samples. The two left-hand graphs represent the TGT curves obtained from a representative rivaroxaban-treated patient (top left graph) and from a representative apixaban-treated patient (bottom left graph) at the different times of their laboratory follow-up (T0 to T4, the corresponding drug concentrations are indicated), whereas the two right-hand graphs represent the TGT curves obtained with the same drugs, but after in-vitro spiking.
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Figure 4: Thrombin generation test curves showing the concentration of thrombin (in nmol/l, Y-axis) according to the time (min, X-axis) after stimulation by a low concentration of tissue factor in the presence of phospholipids. The two upper graphs represent rivaroxaban-treated samples and the two lower graphs represent apixaban-treated samples. The two left-hand graphs represent the TGT curves obtained from a representative rivaroxaban-treated patient (top left graph) and from a representative apixaban-treated patient (bottom left graph) at the different times of their laboratory follow-up (T0 to T4, the corresponding drug concentrations are indicated), whereas the two right-hand graphs represent the TGT curves obtained with the same drugs, but after in-vitro spiking.

Mentions: Effects on kinetic parameters (lag time and peak time) and Cmax resulted in a dramatically altered velocity in all samples from rivaroxaban-treated patients, whereas it was moderately yet significantly affected by apixaban from T2 only (Table 1). Figure 4 shows the TGT follow-up of two representative patients: patient C.L.A. receiving rivaroxaban and patient G.U.E. receiving apixaban, both selected for TGT values near the median values of their treatment group, as shown in Table 1. Whereas the thrombin maximum concentration (Cmax, Table 1 and example in Fig. 4) was dramatically decreased at T2 and T3 with rivaroxaban treatment, it remained almost unchanged in patients receiving apixaban. On the contrary, both drugs delayed thrombin generation, although to a lesser extent for apixaban. Surprisingly, the TGT observed in the ex-vivo samples from patients receiving apixaban only partly reflect the in-vitro alterations observed in plasmas spiked with increasing concentrations of apixaban (from zero = control to 1000 ng/ml), which are more closely in line with those observed with rivaroxaban, both in vitro and ex vivo.


Rivaroxaban and apixaban in orthopaedics: is there a difference in their plasma concentrations and anticoagulant effects?

Freyburger G, Macouillard G, Khennoufa K, Labrouche S, Molimard M, Sztark F - Blood Coagul. Fibrinolysis (2015)

Thrombin generation test curves showing the concentration of thrombin (in nmol/l, Y-axis) according to the time (min, X-axis) after stimulation by a low concentration of tissue factor in the presence of phospholipids. The two upper graphs represent rivaroxaban-treated samples and the two lower graphs represent apixaban-treated samples. The two left-hand graphs represent the TGT curves obtained from a representative rivaroxaban-treated patient (top left graph) and from a representative apixaban-treated patient (bottom left graph) at the different times of their laboratory follow-up (T0 to T4, the corresponding drug concentrations are indicated), whereas the two right-hand graphs represent the TGT curves obtained with the same drugs, but after in-vitro spiking.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664024&req=5

Figure 4: Thrombin generation test curves showing the concentration of thrombin (in nmol/l, Y-axis) according to the time (min, X-axis) after stimulation by a low concentration of tissue factor in the presence of phospholipids. The two upper graphs represent rivaroxaban-treated samples and the two lower graphs represent apixaban-treated samples. The two left-hand graphs represent the TGT curves obtained from a representative rivaroxaban-treated patient (top left graph) and from a representative apixaban-treated patient (bottom left graph) at the different times of their laboratory follow-up (T0 to T4, the corresponding drug concentrations are indicated), whereas the two right-hand graphs represent the TGT curves obtained with the same drugs, but after in-vitro spiking.
Mentions: Effects on kinetic parameters (lag time and peak time) and Cmax resulted in a dramatically altered velocity in all samples from rivaroxaban-treated patients, whereas it was moderately yet significantly affected by apixaban from T2 only (Table 1). Figure 4 shows the TGT follow-up of two representative patients: patient C.L.A. receiving rivaroxaban and patient G.U.E. receiving apixaban, both selected for TGT values near the median values of their treatment group, as shown in Table 1. Whereas the thrombin maximum concentration (Cmax, Table 1 and example in Fig. 4) was dramatically decreased at T2 and T3 with rivaroxaban treatment, it remained almost unchanged in patients receiving apixaban. On the contrary, both drugs delayed thrombin generation, although to a lesser extent for apixaban. Surprisingly, the TGT observed in the ex-vivo samples from patients receiving apixaban only partly reflect the in-vitro alterations observed in plasmas spiked with increasing concentrations of apixaban (from zero = control to 1000 ng/ml), which are more closely in line with those observed with rivaroxaban, both in vitro and ex vivo.

Bottom Line: After 1 week of treatment, the drugs differed: Cmax and Ctrough were closer when apixaban was taken twice daily (83 ± 39 and 58 ± 17 ng/ml) than with rivaroxaban taken once a day (113 ± 67 and 13 ± 20 ng/ml).Rivaroxaban had a greater influence on routine coagulation tests and reduced the maximum thrombin concentration more efficiently, as assessed by the thrombin generation test.Although rivaroxaban and apixaban present apparently similar constant rates, they exhibit significant differences in their concentrations and anticoagulant effects when studied ex vivo in orthopedic patients.

View Article: PubMed Central - PubMed

Affiliation: aLaboratory of Hematology bDepartment of Anesthesiology cLaboratory of Clinical Pharmacology, Bordeaux University Hospital, Bordeaux, France.

ABSTRACT
The aim of this study was to improve knowledge of what happens in the coagulation of orthopaedic patients under rivaroxaban and apixaban, in order to finalize and cross-validate effective measurement methods and to provide arguments for helping to reference one or the other drug in our central pharmacy. One hundred and two patients undergoing total hip or knee replacement were included. Half of them received rivaroxaban and the other half received apixaban. Blood samples (n = 244 with each drug) were taken at Cmax preoperatively and twice a week, apart from the day of the patient's discharge, when Ctrough concentration was targeted. Routine coagulation parameters, and functional and liquid chromatography tandem mass spectrometry assays for measurement of circulating concentrations were studied. The LC-MS/MS assay and the functional assays carried out in patients under routine conditions were highly correlated, apart from low concentrations (<30 ng/ml), which were affected by the variable individual potential to inhibit the exogenous bovine Xa used in the functional assays. After 1 week of treatment, the drugs differed: Cmax and Ctrough were closer when apixaban was taken twice daily (83 ± 39 and 58 ± 17 ng/ml) than with rivaroxaban taken once a day (113 ± 67 and 13 ± 20 ng/ml). Rivaroxaban had a greater influence on routine coagulation tests and reduced the maximum thrombin concentration more efficiently, as assessed by the thrombin generation test. Although rivaroxaban and apixaban present apparently similar constant rates, they exhibit significant differences in their concentrations and anticoagulant effects when studied ex vivo in orthopedic patients.

Show MeSH
Related in: MedlinePlus