Which test to use to measure the anticoagulant effect of rivaroxaban: the anti‐factor Xa assay

Rivaroxaban is a direct and specific factor Xa inhibitor that is licensed for use in venous thromboembolism and in the prevention of ischemic stroke in patients with non-valvular atrial fibrillation. Although coagulation monitoring is unnecessary, there are several clinical settings in which measurement of the anticoagulant activity can be helpful [1,2]. Both the prothrombin time (PT) and anti-FXa activity can be reliably measured. There is a debate over the preferred test. It is generally accepted that anti-FXa activity, in contrast to the PT, is a specific test for rivaroxaban and other FXa inhibitors with a dose–effect relationship [3]. Several techniques have been used, among them the Rotachrom method from Stago, which has to be slightly modified [4], and a new method, Hyphen Biomed, which is specific for direct inhibitors and which is not influenced by indirect inhibitors of FXa (heparins and fondaparinux) [5]. The modified Rotachrom method has been evaluated. The intralaboratory and interlaboratory precision of the measurement was investigated in a field trial involving 20 laboratories. Hyphen Biomed and the modified Rotachrom method were used in parallel in plasmas from orthopedic surgery patients treated with rivaroxaban. The results obtained were comparable. The presence of anti-FXa activity is very rare in untreated patients, whereas several morbidities can influence the PT, which is a non-specific test. Measurement of the PT before starting rivaroxaban treatment should be recommended. During treatment, the PT is not sensitive enough to reliably measure low concentrations of rivaroxaban [6]. Moreover, the International Normalized Ratio (INR) cannot be utilized, as it has been standardized for patients treated with vitamin K antagonists, and the mechanism of action of these drugs is different from that of rivaroxaban. A modification of the International Sensitivity Index of different thromboplastin reagents has been proposed by Tripodi and by Harenberg et al. [7,8]. Further studies with patient plasmas are required, and a therapeutic range expressed in ‘INR.rivaroxaban’ has to be determined. Moreover, for patients switching from warfarin to rivaroxaban, the interpretation of the INR can be difficult, as both drugs affect the PT/INR. A similar problem can be encountered when switching from heparin or fondaparinux to rivaroxaban, the anti-FXa assay being influenced by both drugs. A possible solution to this problem is to use the method that is specific for the anti-FXa measurement of direct inhibitors such as rivaroxaban [5]. Repeatability and reproducibility were determined for this specific method, and favorable results were obtained, with a coefficient of variation of < 5%. Finally, the anti-FXa assay is not available everywhere at all times, but this situation could change in the near future, with the development of apixaban, a direct FXa inhibitor, which has a minimal influence on the PT. For this new anticoagulant, it has been clearly shown that the anti-FXa assay is preferable to the PT [9]. Accurate measurement of rivaroxaban anti-FXa activitym allowing the determination of plasma concentrations expressed in lg L or in ng mL, is feasible when rivaroxaban calibrators and controls are used. The results were comparable when the concentrations were measured by HPLC [10]. In addition, anti-FXa chromogenic assays are less sensitive to sample collection conditions than the PT or activated partial thromboplastin time, [11]. A limitation is that standardization of the anti-FXa assay across reagents and methods is not easily achieved. However, interesting results obtained by Harenberg et al. [8] show that the interassay variability observed with different reagents can be easily reduced by mathematical modeling. A study performed by an ISTH working group on the measurement of apixaban with different anti-FXa chromogenic assays is in progress. Correspondence: Meyer Michel Samama, Biomnis Laboratory, Ivry, France. Tel. : +33 149591603; fax: + 33 149591699. E-mail: MeyerMichel.SAMAMA@biomnis.com