Anti-Xa and Anti-IIa Drugs Alter International Normalized Ratio Measurements: Potential Problems in the Monitoring of Oral Anticoagulants

Abstract

Several of the newly developed anti-Xa and anti-IIa agents have been shown to influence the International Normalized Ratio (INR) values. During phase I trials with normal healthy volunteers and phase II study patients who were given warfarin and concomitant anti-IIa or anti-Xa agents, it has been reported that INR values were falsely elevated. It is of critical importance to know of the effects of these agents on INR to avoid dosage errors. To study the influence of these agents on INR, we used several anti-IIa agents (argatroban, recombinant hirudin, efegatran, and PEG-hirudin) and anti-Xa drugs (pentasaccharides such as fondaparinux and idraparinux, DX-9065a and JTV-803). The anti-IIa drugs were supplemented in citrated plasma at a concentration of 0 to 1 microg/mL level and anti-Xa drugs in the range of 0 to 25 microg/mL. The IC(50) values for each of these agents were calculated. Four different commercially available prothrombin time (PT) reagents were used to perform the PT assays and to calculate the relative INR values. Direct synthetic factor IIa and Xa inhibitors exhibited a concentration-dependent increase in the INR values. Hirudin, efegatran, and PEG-hirudin showed a weaker effect, whereas argatroban showed a much higher elevation of the INR values. Synthetic indirect anti-Xa agents such as the pentasaccharide did not show any effect on the INR values. Furthermore, prothrombin time reagents with high ISI values exhibited disproportionally higher INR values for both the direct anti-Xa and anti-IIa agents. Elevation of INR values has therapeutic implications when non-oral anticoagulant drugs are used in combination with drugs such as warfarin. Because of the false elevation of INR values with some of the non-oral anticoagulant drugs, patients who are on concomitant warfarin therapy should be carefully evaluated for their corresponding INR values for proper dosing. To avoid dosing errors it is best not to use the INR values in the therapeutic monitoring of anti-Xa and anti-IIa agents either in the monotherapeutic or polytherapeutic modalities. These data also warrant the development clinically relevant methods for the monitoring of the concomitant use of newly developed anti-Xa and anti-IIa drugs with oral anticoagulants.

Probing Structural Selectivity of Synthetic Heparin Binding to Stabilin Protein Receptors

“…In contrast, a slow-clearing heparin is more desirable for patients with ongoing use, avoiding repetitive dosing. Indeed, UFH is widely used in surgical procedures and kidney dialysis, whereas LMWH and Fondaparinux are more commonly used as prophylactic agents among high risk patients prone to thrombosis (34,35). Although it is known that the size of the heparin chain plays a role in the rate of clearance in patients, the precise structural requirements for regulating clearance remain uncharacterized.…”

Pharmacokinetics and pharmacodynamics of BIBT 986, a novel small molecule dual inhibitor of thrombin and factor Xa

“…However the concentration-effect relationship differs markedly between drugs (e.g. no slope for lepirudin, almost linear for agatroban and curvilinear for melagatran) [11,12]. BIBT 986 has a linear effect on the INR but the slope of the curve is fairly flat as compared with the other PD parameters (Fig.…”

“…BIBT 986 has a linear effect on the INR but the slope of the curve is fairly flat as compared with the other PD parameters (Fig. 4) or as compared with melagatran or agatroban [11,12]. As a consequence the total variability lowers the degree of correlation between BIBT 986 and the INR (Fig.…”

“…The correlation of TT vs. BIBT 986 concentration was slightly non-linear at low concentrations. Direct inhibitors of FIIa or FXa are able to alter the prothrombin time and thus the INR [11,12]. However the concentration-effect relationship differs markedly between drugs (e.g.…”

“…In Study 1, blood samples for coagulation tests were taken at all, but the 36-h time points as already described for PK. In Study 2, they were taken at: predose ()1 h), 24, 31.98, 32.5, 33, 34, 36, 44, and 56 h after start of infusion; and Study 3 at: predose ()1 h), 2,3,4,5,6,8,12, and 24 h after start of infusion.…”