Anticoagulation Without Monitoring

The new oral anticoagulants dabigatran, rivaroxaban, and apixaban were developed and approved for use without the need for routine laboratory monitoring. With safety and efficacy profiles that are as good as or better than traditional anticoagulants that require monitoring, these medications are attractive alternatives for physicians and patients alike. The introduction of these new oral anticoagulants raises two important issues for the clinical laboratory: (1) under what clinical situations should plasma levels of these drugs be measured, and (2) how do we measure drugs designed to be used without monitoring when approved assays are not available and the need is for rapid turnaround times to help in the assessment of acute bleeding or thrombosis? This issue of the American Journal of Clinical Pathology contains two important review articles related to the pathologist’s and clinical laboratory’s roles regarding the new oral anticoagulants dabigatran, rivaroxaban, and apixaban.1,2 They describe methods used for measuring plasma levels, potential approaches to reversal, and types of consultations and questions that pathologists may face related to these medications. The first generation of anticoagulants, warfarin and unfractionated heparin, requires continuous monitoring to minimize the risk of bleeding and thrombosis. This is an early example of precision medicine and patient-specific adjustment of levels to optimize therapy. Warfarin is monitored primarily with the prothrombin time (PT)/international normalized ratio on a weekly to monthly basis. Unfractionated heparin was initially monitored daily with the activated partial thromboplastin time (aPTT), but concerns arose related to the lack of specificity of aPTT, including interference from high factor VIII, lupus inhibitors, low vitamin K–dependent factor levels, and other issues. This concern led to the development of more specific assays for heparin activity, the anti–factor Xa method (anti-Xa). The review article by Wool and Lu1 describes the different factor X–related assays and how they are used for monitoring anticoagulants. Controversy continues to exist on whether unfractionated heparin monitoring is better using aPTT vs anti-Xa. The next anticoagulant introduced was low-molecular-weight heparins (LMWHs). These medications were designed, tested in clinical trials, and approved for use without monitoring. Typically, they are given once or twice daily and can replace unfractionated heparin in many situations. Ease of use, safety, efficacy, and lack of monitoring offset the higher cost of the medication itself. However, soon after their introduction, there was a desire to measure the level of LMWH in some patients, even though they were approved for use without monitoring. One issue involving drugs such as LMWH and the new oral anticoagulants is when it is appropriate to measure levels of a drug approved for use without monitoring. For some types of surgery, physicians want to know if the drug has cleared before proceeding. In these situations, an assay that could detect the presence or absence of the drug may be sufficient, with a good detection limit being most important.3 In patients who are bleeding while taking anticoagulants, physicians want to know when the drug has cleared and is therefore no longer implicated as a cause of bleeding, as well as whether the patient is overdosed vs therapeutic on the drug, since this may indicate how long the drug will take to clear. Similarly, if the patient develops thrombosis while taking the drug, physicians want to know whether the patient was compliant—actually taking the drug—and whether the level was therapeutic at the time of the thrombosis. Another situation where drug levels are ordered is in patient groups that have not been studied in clinical trials and in which there are no approved dose recommendations. These groups often include the elderly, neonates, children, pregnant women, and obese patients. Recommendations are provided for dosage changes in patients with moderate renal insufficiency, but in patients with worse renal function or with a substantial change in renal function, drug levels could help determine the appropriate dosage. Clinical measurement of a drug level requires an assay with an acceptable detection limit, precision, and linear range; appropriate calibrators; and a therapeutic range for interpretation. This was not too difficult for LMWH since the anti-Xa assay for unfractionated heparin was adapted to measure LMWH, calibration used the drug itself, and studies became available reporting recommended therapeutic ranges.4–6 Clinical measurement of the new oral anticoagulants is more difficult, as discussed in the review articles.1,2 For dabigatran and other direct thrombin inhibitors, the aPTT can be used to estimate levels but has a curvilinear response and suffers from all the same interferences seen for heparin monitoring. The standard thrombin time is too sensitive to measure direct thrombin inhibitor levels but can be used to detect the clearance or absence of a direct thrombin inhibitor. Ecarin clotting times (ECTs) can be used but are not available in most hospitals. The plasma diluted thrombin time has the following characteristics: an advantage of using the same reagent as the standard thrombin time, a linear response across the therapeutic range, speed, and, by diluting the sample with normal plasma, an ability to eliminate most of the interferences seen with the aPTT.7,8 Commercial dabigatran calibrators are available but not approved for clinical use in the United States, and therapeutic ranges are not available. The best that can be provided are typical levels during standard therapy.9 Rivaroxaban and apixaban can be measured using modified anti-Xa methods. Commercial calibrators are available for rivaroxaban but not approved for clinical use in the United States, and therapeutic ranges are not available for either oral anti-Xa drug.9,10 One additional concern with using these new oral anticoagulants is the lack of a reversal agent for use in bleeding patients. In their review, Winkler and Tormey2 discuss possible treatment options for patients taking direct thrombin inhibitors. Even though their safety profiles were often better overall than that of warfarin, this is little consolation for the individual taking one of these medications who has bleeding or the need for emergent surgery with a high bleeding risk. Because their major advantage and government approval were for use without monitoring, companies marketing these drugs did not develop routine methods for measuring them. Current product inserts for dabigatran suggest that in situations of possible overdose, “Measurement of aPTT or ECT may help guide therapy,” but no therapeutic ranges are given.11 For rivaroxaban, there is no mention of measuring levels, and no ranges are given.12 For apixaban, the PT and aPTT are reportedly “subject to a high degree of variability...not useful in monitoring,” while measurements of anti-Xa activity are reported to be “concentration dependent” but “not recommended.”13 This leaves clinical laboratories in the difficult position of fielding requests from physicians for a rapidly available clinical assay for use in some patients and needing to develop an in-house method with limited availability of assays, calibrators, and therapeutic ranges. The accompanying review articles provide help in developing these new assays and consulting with physicians.