Current and Emerging Direct Oral Anticoagulants: State-of-the-Art.

Anticoagulant drugs comprise a specific subcategory of antithrombotic agents that act to inhibit blood coagulation at various stages, reducing clot development and ultimately lowering the risk of developing new-onset or recurrent thrombosis. Although the long history of anticoagulant drugs has been characteristically shaped by coumarin and heparin derivatives, a new generation of direct oral anticoagulants (DOACs), which specifically inhibit thrombin or activated factor X, combine many advantages of their progenitor drugs, and hence are prepotently revolutionizing the landscape of antithrombotic therapy. Several drugs (apixaban [BMS-562247], dabigatran [BIBR953], edoxaban [DU-1766], rivaroxaban [BAY 59-7939]) have already received widespread approval by national or supranational medicinal agencies. This narrative article provides a state-of-the-art for these and for several other DOACs at different stages of clinical evaluation (betrixaban, darexaban, eribaxaban, letaxaban, nokxaban), and certain others whose development has been discontinued (AZD-0837, fidexaban, LY517717, odiparcil, otamixaban, TTP889, and ximelagatran). What clearly emerges from our analysis is that DOACs sharing very similar mechanisms of action are still characterized by different efficacy and safety profiles. This not only depends on biochemical, biological, and pharmacokinetic characteristics, but also on lack of standardization between different clinical trials in terms of targeted disease, patient recruitment, sample size, duration and endpoints, as well as lack of harmonization around procedures used for drug licensing. These factors contribute to challenging the minds of physicians, who may find difficulty navigating their way through multiple indications, different pharmacological profiles, various side effects, and specific drug-to-drug interactions. Such considerations also burden laboratory professionals, who may face organizational and economic challenges in developing and/or implementing multiple assays to assess the pharmacodynamics (effect on coagulation) or pharmacokinetics (drug levels) of DOACs.

Measuring Direct Oral Anticoagulants.

Direct oral anticoagulants (DOACs) can be quantified using methods that can be performed in any clinical or research laboratory using manual or automated instrument platforms. Dabigatran etexilate, the oral direct thrombin inhibitor, can be quantified by drug-calibrated clot or chromogenic-based assays using either thrombin or ecarin as substrates. Oral direct anti-Xa inhibitors, such as rivaroxaban, apixaban, and edoxaban, can be quantified with drug-calibrated anti-Xa kits or reagents as typically used for measuring heparins (unfractionated, low molecular weight, or pentasaccharides).

Comparison of anti-Xa and dilute Russell viper venom time assays in quantifying drug levels in patients on therapeutic doses of rivaroxaban.

CONTEXT: Rivaroxaban is a new oral anticoagulant that functions as a direct anti-Xa inhibitor. Although routine monitoring is not required, measurement of plasma concentrations may be necessary in certain clinical situations. Routine coagulation assays, such as the prothrombin time and, to a lesser degree, activated partial thromboplastin time, correlate with drug concentration, but because of reagent variability, these methods are not reliable for determining rivaroxaban anticoagulation. OBJECTIVE: To compare different methods and calibrators for measuring rivaroxaban, including the chromogenic anti-Xa assay, which, when calibrated with a rivaroxaban standard, may be more appropriate for determining anticoagulation. DESIGN: We compared measured rivaroxaban concentrations with the same anti-Xa kit but used different calibrators, with different anti-Xa kits but the same calibrators, with antithrombin-supplemented anti-Xa kit versus nonsupplemented kits, and with 2 methods based on rivaroxaban-calibrated, high-phospholipid, dilute Russell viper venom time. Regression and paired t test statistics were used to determine correlation and significant differences among methods and calibrator sources. RESULTS: Although there was strong correlation, statistically significant biases existed among methods that report rivaroxaban levels. A single-source calibrator did not alleviate those differences among methods. High-phospholipid Russell viper venom reagents correlated with rivaroxaban concentration but were not better than chromogenic anti-Xa methods. CONCLUSIONS: Rivaroxaban-calibrated, anti-Xa measurements correlate well, but the clinical significance of the variation with rivaroxaban measurements is uncertain. The antithrombin-supplemented, anti-Xa method should be avoided for measuring rivaroxaban.

Performance of coagulation tests in patients on therapeutic doses of rivaroxaban. A cross-sectional pharmacodynamic study based on peak and trough plasma levels.

Knowledge of anticoagulation status during rivaroxaban therapy is desirable in certain clinical situations. It was the study objective to determine coagulation tests most useful for assessing rivaroxaban's anticoagulant effect. Peak and trough blood samples from 29 patients taking rivaroxaban 20 mg daily were collected. Mass spectrometry and various coagulation assays were performed. "On-therapy range" was defined as the rivaroxaban concentrations determined by LC-MS/MS. A "misprediction percentage" was calculated based on how often results of each coagulation assay were in the normal reference range, while the rivaroxaban concentration was in the "on-therapy" range. The on-therapy range was 8.9-660 ng/ml. The misprediction percentages for prothrombin time (PT) and activated partial thromboplastin time (aPTT), using multiple reagents and coagulometers, ranged from 10%-52% and 31%-59%, respectively. PT, aPTT and activated clotting time (ACT) were insensitive to trough rivaroxaban: 59%, 62%, and 80% of samples had a normal result, respectively. Over 95% of PT and ACT values were elevated at peak. Four different rivaroxaban calibrated anti-Xa assays had R² values >0.98, demonstrating strong correlations with rivaroxaban drug levels. In conclusion, PT, aPTT and ACT are often normal in patients on therapeutic doses of rivaroxaban. However, PT and ACT may have clinical utility at higher drug plasma levels. Rivaroxaban calibrated anti-factor Xa assays can accurately identify low and high on-therapy rivaroxaban drug levels and, therefore, have superior utility in all clinical situations where assessment of anticoagulation status may be beneficial.