Practical guidance on the use of laboratory testing in the management of bleeding in patients receiving direct oral anticoagulants

Abstract

Direct oral anticoagulants (DOACs) have demonstrated a favorable benefit–risk profile in several thromboembolic disorders and are increasingly used in routine clinical practice. A number of real-world studies on DOACs are ongoing, and data published so far have shown broadly similar outcomes to those demonstrated in the respective phase III trials. Despite their beneficial attributes, bleeding risk (as with any other anticoagulants) is often a concern for physicians when prescribing DOACs, particularly in elderly patients, those with significant comorbidities, and other high-risk patient populations. Although the absence of routine coagulation monitoring is an advantage of the DOACs, measuring their anticoagulant effect and/or plasma drug levels may be helpful in certain clinical scenarios to help patient management and improve outcomes. In this paper, practical guidance and recommendations are provided for clinical situations in which the test results may aid clinical decision-making, including patients with life-threatening bleeding events, patients without bleeding but with test results indicating a risk of bleeding, for those patients with a suspected thromboembolism while receiving a DOAC, or prior to patients undergoing elective or urgent surgical procedures. Finally, appropriate monitoring of the DOACs could be of substantial benefit to patients, and there is a high potential for development in this area in the future.

Apixaban and rivaroxaban anti-Xa level utilization and associated bleeding events within an academic health system

“…Commercially available anti-Xa chromogenic assays may be utilized for FXaI levels with appropriate drug calibrators [ 8 , 9 ], and have demonstrated good correlation between plasma FXaI concentration and anti-factor Xa activity across a range of plasma concentrations [ 10 ]. Some researchers have attempted to establish “on therapy” anti-Xa level ranges for apixaban and rivaroxaban in a pragmatic setting [ 11 ], whereas other pharmacokinetic studies conducted in healthy volunteers suggest expected plasma levels based on FXaI type, dose, and time since last dose [ 12 , 13 ]. Certain clinical scenarios such as breakthrough thrombosis, bleeding events, and hepatic and renal insufficiency may warrant assessment of physiologically relevant FXaI concentrations [ [14] , [15] , [16] , [17] , [18] ], and there is some evidence correlating plasma concentrations of certain direct oral anticoagulants (DOAC) such as dabigatran and edoxaban with bleeding events [ 19 , 20 ].…”

Direct oral anticoagulants: When to consider laboratory testing?

“…Frequently mentioned acute situations where knowledge of a DOAC activity level in blood may be helpful concern bleeding, thrombosis, urgent invasive procedures, and thrombolysis, while on DOAC therapy . Other potential settings are extreme body weight, adherence to medication, suspected overdose, major decline in renal function, (contra), acute illness, and indications for antidote administration …”

“…). In many cases, there will be a need to obtain an activity level, and for that purpose, quantitative assays have been developed . Two issues still require attention: First, these assays take more time and are not available 24/7 in every hospital; second, it is imperative to be aware of the approximate timing between drug intake and blood collection in order to interpret any level against published on‐therapy ranges.…”

“…In the absence of an immediately available quantitative assay for rivaroxaban, the attending physician decided to continue with rivaroxaban at an increased dose, as used for treatment of acute DVT, that is, 15 mg bd, after obtaining a blood sample for additional testing. Afterward, it was found that the patient had an anti‐Xa level of 333 μg/L (by calibrated chromogenic anti‐Xa assay; time point between peak and trough), which was at the high end of the expected on‐therapy range (5‐95th percentile 184‐343 μg/L for a peak level of a 20 mg od dose). The eGFR was estimated with the Modification of Diet in Renal Disease (MDRD) formula: 59 mL/min; of note, MDRD is the assessment for renal function in our hospital.…”

“…In his discharge letter to the general practitioner (GP), the cardiologist wrote “I recommend control of liver and renal function after 1 year and in case the clearance becomes in the range of 15‐30 mL/min, please adjust the dose to 2.5 mg bd”. A few months later, she again developed microcytic anemia associated with upper gastrointestinal blood loss confirmed by gastroscopy (ulcer); at that moment, her eGFR had deteriorated to 21 mL/min; additional routine testing included PT 12.6, aPTT 26 (both within normal ranges), and anti‐Xa activity of 832 μg/L (by calibrated chromogenic anti‐Xa assay) at trough time, clearly elevated (on‐therapy trough apixaban levels 41‐230 μg/L). After cessation for a few days, apixaban was resumed in an adjusted dose of 2.5 mg bd, on the advice of the cardiologist, but a trough anti‐Xa level obtained a month later showed a persistently elevated level of 376 μg/L.…”