Monitoring of Anticoagulant Therapy in Heart Disease: Considerations for the Current Assays

Clinicians should be aware of new developments to familiarize themselves with pharmacokinetic and pharmacodynamic characteristics of new anticoagulant agents to appropriately and safely use them. For the moment, cardiologists and other clinicians also require to master currently available drugs, realizing the mechanism of action, side effects, and laboratory monitoring to measure their anticoagulant effects. Warfarin and heparin have narrow therapeutic window with high inter- and intra-patient variability, thereby the use of either drug needs careful laboratory monitoring and dose adjustment to ensure proper antithrombotic protection while minimizing the bleeding risk. The prothrombin time (PT) and the activated partial thromboplastin time (aPTT) are laboratory tests commonly used to monitor warfarin and heparin, respectively. These two tests depend highly on the combination of reagent and instrument utilized. Results for a single specimen tested in different laboratories are variable; this is mostly attributable to the specific reagents and to a much lesser degree to the instrument used. The PT stands alone as the single coagulation test that has undergone the most extensive attempt at assay standardization. The international normalized ratio (INR) was introduced to “normalize” all PT reagents to a World Health Organization (WHO) reference thromboplastin preparation standard, such that a PT measured anywhere in the world would result in an INR value similar to that which would have been achieved had the WHO reference thromboplastin been utilized. However, INRs are reproducible between laboratories for only those patients who are stably anticoagulated with vitamin K antagonists (VKAs) (i.e., at least 6 weeks of VKA therapy), and are not reliable or reproducible between laboratories for patients for whom VKA therapy has recently been started or any other clinical conditions associated with a prolonged PT such as liver disease, disseminated intravascular coagulation, and congenital factor deficiencies. In contrast to marked progress in the standardization of PT reagents for INR reporting, no standardization system has been globally adopted for standardization of PTT reagents. Recently College of American Pathologists recommend that individual laboratories establish their own therapeutic range by using aPTT values calibrated against accepted therapeutic unfractionated heparin (UFH) levels calibrated against accepted therapeutic UFH levels performing anti-Xa test (which is the most accurate assay for monitoring UFH therapy). Herein, we review recent data on the monitoring of conventional anticoagulant agents. Marked interlaboratory variability still exists for PT, INR, and PTT tests. Further research should be focused on improving the standardization and calibration of these assays.